Register or Submit a manuscript.
Quick Link
OBM Genetics

(ISSN 2577-5790)

OBM Genetics is an international Open Access journal published quarterly online by LIDSEN Publishing Inc. It accepts papers addressing basic and medical aspects of genetics and epigenetics and also ethical, legal and social issues. Coverage includes clinical, developmental, diagnostic, evolutionary, genomic, mitochondrial, molecular, oncological, population and reproductive aspects. It publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.

Publication Speed (median values for papers published in 2023): Submission to First Decision: 5.1 weeks; Submission to Acceptance: 17.0 weeks; Acceptance to Publication: 7 days (1-2 days of FREE language polishing included)

Current Issue: 2024  Archive: 2023 2022 2021 2020 2019 2018 2017
Open Access Review

Novel Insights into Epigenetic Control of Autophagy in Cancer

Sana Parveen 1,2, Suroor Fatima Rizvi 1,3, Adria Hasan 1,3, Uzma Afaq 1,2, Snober S. Mir 1,2,*

  1. Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India

  2. Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow, 226026, India

  3. Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow, 226026, India

* Correspondence: Snober S. Mir

Academic Editor: Lunawati L Bennett

Special Issue: Cancer Genetics and Epigenetics Alterations II

Received: June 28, 2022 | Accepted: October 16, 2022 | Published: November 08, 2022

OBM Genetics 2022, Volume 6, Issue 4, doi:10.21926/obm.genet.2204170

Recommended citation: Parveen S, Rizvi SF, Hasan A, Afaq U, Mir SS. Novel Insights into Epigenetic Control of Autophagy in Cancer. OBM Genetics 2022; 6(4): 170; doi:10.21926/obm.genet.2204170.

© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

The autophagy mechanism recycles the damaged and long-standing macromolecular substrates and thus maintains cellular homeostatic and proteostatic conditions. Autophagy can be an unavoidable target in cancer therapy because its deregulation leads to cancer formation and progression. Cancer can be controlled by regulating autophagy at different genetic, epigenetic, and post-translational levels. Epigenetics refers to the heritable phenotypic changes that affect gene activity without changing the sequence. Modern biology employs epigenetic alterations as molecular tools to detect and treat a wide range of disorders, including cancer. However, modulating autophagy at the epigenetic level may inhibit cancer growth and progression. Epigenetics-targeting drugs involved in preclinical and clinical trials may trigger antitumor immunity. Here, we have reviewed some experimental evidence in which epigenetics have been used to control deregulated autophagy in cancerous diseases. Furthermore, we also reviewed some current clinical trials of epigenetic therapy against cancer. We hope that this information can be utilized in the near future to treat and overcome cancer.

Graphical abstract

Click to view original image

Keywords

Autophagy; genetic; epigenetic; cancer therapy

1. Introduction

Despite breakthroughs in technology, research, and medication over the previous few decades, cancer remains a global challenge. Cancer is currently the world’s largest cause of death, contributing to 10 million deaths by 2020 [1]. Traditional cancer treatments such as chemotherapy, surgery, radiotherapy, and immunotherapy are the mainstream therapeutic approaches for cancer. However, they come with a longer list of disadvantages, such as damage to normally growing healthy cells, long-term side effects, systemic toxicity, structural distortions, drug resistance by tumor cells, and psychological problems. Furthermore, side effects can limit the use of anticancer drugs, lowering a patient’s quality of life [2,3]. Thus, despite advances in cancer research, diagnosis, and treatment, searching for new therapeutic agents and therapies remains a hot topic in cancer research [4].

Over the last few years, discoveries in cancer biology have increased the knowledge of many significant biomarkers of cancer, including changes in cell physiological processes such as programmed cell death, control at cell cycle checkpoints, immunological modulation, and angiogenesis [5]. Cancer is known to be caused by genetic and epigenetic factors [6]. Changes at the epigenetic level regulate the expression of various genes by controlling the accessibility of promoter sites to transcriptional factors. Different epigenetic modifications like histone modifications, DNA methylation, and microRNA changes may modulate cell growth cycle, apoptosis, and autophagy [6,7]. Abnormal gene silencing mediated by epigenetic changes is also a significant factor in tumorigenesis and development.

Autophagy is a catabolic process that is critical in the initiation and development of cancer [8]. Autophagy interacts with cell metabolic reactions, cell survival, and the turnover of proteins and organelles at multiple levels, implying that autophagy in cancer has paradoxical and complicated roles [5]. It has been suggested that the deregulation of autophagy is controlled by various signaling pathways, including epigenetic control. Although the role of epigenetic regulation in autophagy is larger unknown [6].

Cancer can be regarded as a disease controlled by multiple players. Hence, targeting the relationship between different cellular mechanisms may yield a better therapeutic response instead of targeting only one cellular mechanism. So in this study, we discuss the epigenetic modulation of autophagy in cancer.

2. Epigenetics and Cancer

The study of changes in gene expression that are heritable and occur without any changes in the gene sequence is known as epigenetics [9]. C. H. Waddington coined epigenetics in 1942 to describe how heritable phenotypic expression alters gene expression and potentially reversible changes in chromatin structure and DNA methylation. An essential feature of epigenetic mechanisms is that they can change gene functions in response to exogenous stimuli. They also provide a means for steadily disseminating gene activity states between generations [9,10,11].

Epigenetic mechanisms have significant roles in maintaining gene expression patterns in specific tissues and normal mammalian development [12]. This reprogramming is a heritable trait but can be reversed [13] and affects cell growth, proliferation, differentiation, and migratory properties. Cancer emergence, progression, and treatment responsiveness are all linked to aberrant epigenetic profiles [14], so it’s not surprising that these processes are involved. Despite the promise of epigenetic therapeutics, further investigation into the precise pathways involved is necessary for the safe and efficient development and application of epigenetic therapeutics, either alone or in combination with existing therapies [15]. DNA methylation, modification of histone tails, RNA-associated silencing, and genomic imprinting are the four types of epigenetics-mediated gene silencing [Figure 1]. Other factors, such as the environment and xenobiotics can also result in gene silencing. Still, DNA methylation and histone modification of chromatin are the two most important changes responsible for developing malignant diseases [16].

Click to view original image

Figure 1 Epigenetic mechanisms. Epigenetic changes significantly direct the abnormal expression of oncogenes that drive cell malformation and cancer development. Changes in DNA methylation patterns were the first epigenetic hallmarks linked to carcinogenesis and changes in gene expression through the silencing of tumor suppressor genes (TSGs) [17].

2.1 DNA Methylation

Adding a methyl group to a cytosine-guanine dinucleotide (also called a “CpG site”) is the most common type of epigenetic modification [18]. CpG sites are usually found at the end of genes, occupying about 60% to 70% of gene promoters in vertebrates that remain unchanged over time [19]. This is because DNA methylation is affected by both genetic and environmental factors [18]. Various cellular processes are influenced by epigenetic changes in the genome or DNA methylation, which affects embryo growth, mRNA synthesis, chromatin structure, and stability of chromosomes and may also inactivate the X chromosome [20]. It also helps control gene expression by recruiting proteins that help stop cell growth or block transcription factors, which help control gene expression. Demethylation and methylation are processes that significantly control epigenetic changes. DNA methylation affects the binding of transcription factors and the accessibility of regulatory regions in DNA, affecting gene expression [21]. DNMTs i.e., DNA methyltransferases, commonly mark DNA by attaching a CH3 group to the fifth carbon of a cytosine residue in a CpG dinucleotide, resulting in 5-methylcytosine [21,22] (Figure 2a).

Click to view original image

Figure 2 (a) CH3 group from S-adenyl methionine (SAM) to the 5th carbon of a cytosine residue to make 5-methylcytosine; (b) Methylation through DNMT1 and de-novo methylation through DNMT 3a/3b.

2.1.1 DNA Methyltransferases (DNMTs)

Dnmt1, Dnmt2, Dnmt3A, and Dnmt3B are members of the mammalian DNMT family. This family is split into two groups: maintenance and de novo methyltransferases. CH3 groups are added to the hemi-methylated DNA by the maintenance of DNMT1 during DNA synthesis, whereas CH3 groups are added to the CpG dinucleotide sites of DNA molecule by de novo DNMT3A and DNMT3B (Figure 2b) [23]. The conventional DNA methylation pattern in somatic cells is maintained during cell division by DNMT1 [24,25,26]. DNMT1 adds CH3 group to the new DNA strand at the fifth position of the cytosine base within the CpG dinucleotides by being a component of the DNA replication complex thereby maintaining methylation of the newly formed DNA molecule [27]. Isoforms of DNA methyltransferases, associated with the DNMT1 gene, have been identified in somatic cells, oocytes, pachytene sperm cells, and preimplantation embryos. These isoforms are produced by another use of different first exons of the DNMT1 primary transcript, which can be found in the DNMT1 gene. The role of enzymes DNMT3A and DNMT3B in establishing an additional methylation style in genomic DNA has been identified [23,24,28].

Dnmt3a and Dnmt3b can make novel methylation patterns in unchanged DNA, which is why they are called de novo DNMT. When DNA is being made, Dnmt1 is used to reproduce the pattern of DNA methylation from the parent DNA template onto the new daughter strand [22].

DNMTs have an important function in the methylation of mammalian genomic DNA. The expression of the DNMTs is much higher in breast, colon, endometrium, prostate, stomach cancer, and uterine leiomyoma than in other types of cancers [29]. And the aberrant DNA methylation has been found in many cancers, like breast, oral, gastric, colon, liver, lung, and pancreatic cancers [30,31,32,33,34,35,36].

Hypermethylation, hypomethylation, and loss of imprinting are three types of changes that can happen to the DNA. Changes in the methylation pattern of promoter sequences, such as the hypermethylation or hypomethylation in TSGs and proto-oncogenes, respectively, are linked to cancer malignancy [34,35,36,37].

2.1.2 DNA Hypermethylation

In the last 10 years, a new way for tumor growth has been found: the hypermethylation of TSGs. Tumor series show that hypermethylation of TSGs may play a role in the oncogenesis in children. Thus, these epigenetic changes could be used to indicate the disease, and genes that control methylation should be considered as possible new therapeutic targets [38].

DNA hypermethylation is a term that primarily refers to the acquisition of methylation at places that aren’t normally methylated. This kind of methylation happens mainly in the promoter region of CpG sites. A CpG island is a DNA sequence (more than 200 bp) with >50% GC content. Expected CpG ratio of more than 0.6 [39,40], is called “abnormal promoter CpG island hypermethylation”, which has been linked to the loss of gene function and the stabilization of transcriptional repression, which happens mostly in TSGs [41,42]. Most of the changes affecting gene regulation due to DNA methylation are found at the non-promoter sites near CGIs (approx. 2 kb long with low GC density) [43]. Most tissue-specific DNA methylation is found near CGI sites instead of CpG islands [44]. This data supports the concept that epigenetic changes like DNA methylation have crucially important roles in cancer development because they affect the differentiation of specific tissues.

2.1.3 DNA Hypomethylation

The loss of DNA methylation in genome-wide areas is the most common cause of DNA hypomethylation. Feinberg and Vogelstein first found that in two different types of cancers, a significant number of genes were methylated compared to normal cells [45]. Many studies have reported that DNA hypomethylation has been found in many different types of tumors, including skin, colorectal, and gastric cancers [46]. DNA hypomethylation takes place in several parts of the genome, like repetitive elements, retrotransposons, and introns which causes instability in the genome [42]. In repeat sequences, DNA hypomethylation occurs by an advanced rate of chromosomal reorganizations and by an increased chance of translocation in retrotransposons to other parts of the genome [47,48]. The amount of DNA methylation increases with the growth of a tumor from benign to malignant and invasive phenotype [49].

2.1.4 Loss of Imprinting

Loss of imprinting occurs when one of the two parental alleles doesn’t have the same amount of DNA methylation as the other. Susceptibility toward cancer, such as colorectal cancer, increases with the loss of IGF2 imprinting, which has also been observed in different cancers [50].

2.2 Chromatin Remodeling

The human genome contains chromatin, a complex of DNA and protein condensed into nucleoprotein form [51]. The nucleosome is the basic component of chromatin with an octamer of histones from packaging two molecules each of H2A, H2B, H3, and H4. 147 base pairs of DNA wound twice around this octamer of histones to form a nucleosome. ATP-dependent chromatin remodeling complexes transfer histone octamers among the DNA molecules and thus mediate the density and position of histone octamers along the molecule of DNA [52,53]. Poly-ADP ribosylation, ubiquitination of histone amino termini and addition of acetyl, methyl, and phosphate groups regulate the affinity of histones for DNA and proteins associated with chromatin [54]. The availability of DNA for mRNA synthesis, DNA synthesis, DNA methylation, recombination, and repair is controlled by the positions of histones which shapes the genome into either open or condensed chromatin. These modifications, i.e., positioning of histones, form a histone code or epigenetic ‘memory’. This memory is transferred to the daughter cells from the parent cells [55]. Cancer is caused by the mutatable changes in genes affecting the functional characteristics of chromatin-remodeling complexes [56].

2.3 Histone Modification

Proteins of nucleosomes can also be changed by covalent bonds besides CpG methylation of DNA. Four pairs of histones form the core set of histones in nucleosomes i.e., H2A, H2B, H3, and H4 [57]. When DNA gets condensed in a nucleosome structure, it is called chromatin. Histones are alkaline proteins that help build chromatin. These parts of the cellular machinery control how genes are turned on and off [58,59]. Histones are the main determinants of chromosome shape and stability, and they can be changed after they’ve been made. These modifications can change chromatin, leading to gene expression modifications. H3 lysine 4 trimethylation is a hallmark of active promoters, while H3 lysine 27 trimethylation and H3 lysine 9 trimethylation are signatures of histones flanking inactive promoters [57,60]. Additionally, a tight association exists between enhancers and regions consisting of H3 lysine 4 monomethylation [61]. Cancer cells commonly have an excess of repressive histone marks compared to normal cells, which can lead to the suppression of some major TSGs [62]. Post-translational histone modifications modulate chromatin conformation and accessibility and thus control gene expression. Extracellular signals can target specific residues at histone tails by the families of histone-modifying enzymes [63]. Structurally, histones have a C-terminal domain and an N-terminal tail. The N-terminal tail through various post-translational modifications (PTMs) that alter chromatin conformation like methyl, acetyl, phosphate, and small ubiquitin-related modifier protein (SUMO) group addition, ubiquitylation and ADP-ribosylation on specific residues [58,59].

2.3.1 Acetylation

Acetylation refers to the reversible attachment of an acetyl group to the ε-amino group of lysine residues regulated by histone acetyltransferases and deacetylases, thereby leading to the activation of gene transcription. Acetyl group is added or removed by histone acetyltransferases and histone deacetylases respectively [64]. Acetylation or deacetylation has been reported to affect DNA damage repair and synthesis, mRNA synthesis and cancer cell invasiveness. In all these alterations, histone acetylation can be controlled dynamically by histone acetyltransferases and histone deacetylases. Histone deacetylases (HDACs) maintain transcriptional silencing by adding or removing acetyl groups at the lysine residues present at the N-terminal of histones, however, HATs activate gene transcription [65,66].

2.3.2 Methylation

Histone methylation i.e. the attachment of methyl groups to lysine and/or arginine residues at histone terminal region/tail is a dynamic process with main roles in differentiation and development. Histone methyl transferases trigger this process, however, histone demethylases (HDMs) reverse this progress due to the removal of the added methyl groups. Methylation can be classified as activating or repressive depending on the modified residue [67].

2.3.3 Phosphorylation

Histone phosphorylation occurs primarily at serine, threonine, and tyrosine residues of histone tail, which is linked with transcription and an accessible chromatin conformation. Histone H3 phosphorylation at tyrosine 41 residue primarily occurs at active promoter sites flanking transcription initiation sites along with the H3 lysine 4 trimethylation mark [68].

Most current studies focus on acetylation, methylation, and phosphorylation of histones, however many other histone modifications have also been studied like ubiquitination, tyrosine hydroxylation, lysine crotonylation, propionylation, butyrylation, biotinylation, neddylation, O-GlcNAc, sumoylation, ADP ribosylation, proline isomerization, N-formylation, and citrullination [63].

2.4 Non-Coding RNA (NcRNA)-Associated Gene Silencing

NcRNAs are widely expressed in organisms and belong to a class of RNAs that do not express any protein. NcRNAs are categorized into 2 groups: housekeeping and regulatory NcRNAs. Regulatory NcRNAs can be subclassified according to their size into short NcRNAs (including small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs)), mid-size NcRNAs and long non-coding RNAs (lncRNAs) where short NcRNAs have ˂50 nucleotides, mid-size NcRNAs range between 50-200 nucleotides, and lncRNAs have >200 nucleotides [69,70].

Most of the NcRNAs were thought to be “junk RNAs”. But recently the mutations in ncRNAs have been implicated in diseases like cancer [71]. NcRNAs account for ~90% of human genome-derived RNAs which include lncRNAs, pseudogene transcripts, and circular RNAs (circRNAs) whereas miRNAs, piRNAs and tRNA-derived small RNAs (tsRNAs), are NcRNAs of 200 bp in length [72]. Around 2,000 miRNAs have been discovered in humans which control physiological and developmental processes such as cell growth and differentiation, transcriptional regulation, autophagy and apoptosis, by binding to the 3’ untranslated region of the mRNA and thus suppress the expression of genes at the post-transcriptional level [73,74,75]. For example, one study provided evidence that MiR-30a expression suppressed Beclin1 expression, leading to the inhibition of autophagy in the medulloblastoma [74]. As well as another study showed that miR-34a physically interacts with and functionally targets tRNA precursors and suppresses breast carcinogenesis, at least in part by lowering the levels of tRNAi Met through Argonaute 2 (AGO2)-mediated repression, thereby inhibiting breast cancer cells proliferation and inducing cell cycle arrest and apoptosis [75]. In this way, miRNAs are involved in cancer regulation by controlling cellular differentiation and apoptosis, or by modulating the activity of oncogenes and/or TSGs [76]. Regulation of >50% of miRNA genes, present in genomic regions of cancer, can contribute to tumorigenesis, invasion, metastasis and drug-resistant phenotypes [77,78]. So, different epigenetic modulations (DNA methylation, histone modifications, and miRNAs) may control cell cycle, apoptosis and autophagy.

3. Autophagy

Autophagy is fundamental (Greek for “self-eating”) [79] and a conserved trafficking pathway mainly regulated by environmental conditions. Autophagy is activated during starving conditions and also in response to specific hormones in mammalian cells [80]. During autophagy, some portion of cytoplasm is captured into a vesicle called autophagosome and directed for degradation to the lysosome. There are three types of autophagy processes, namely microautophagy, macroautophagy, and chaperone-mediated autophagy [81]. Among all the three types of autophagy, macroautophagy (hereafter referred to as autophagy) is the major pathway for energy and metabolites supply during nutrient-deprived conditions [82]. Dysfunctional autophagy has been reported may cause different types of mammalian diseases [79].

There are around 42 Atg genes that play a regulatory role in autophagy. The target of rapamycin (TOR) kinase is one of the important players which gets inactivated in response to different stress stimuli. Hypophosphorylated Atg13 formed as a result of TOR Kinase inactivation and forms a complex of Atg13-ATG1-ATG17. The crosstalk between Atg13-Atg1-Atg17 is required for the kinase activity of Atg1 in regulating Atg9, which in turn facilitates phagophore membrane assembly by extracting phospholipids from different organelles membrane. Interaction of class III PI (phosphoinositide) 3 kinases with Beclin-1 leads to the production of phosphatidylinositol-3-phosphate (PI3P) for the formation of autophagosome during elongation [83]. Atg7 and Atg10 are responsible for the conjugation of Atg12 to Atg5, followed by pairing with Atg16 to form the Atg5-Atg12-Atg16 complex, which in turn is required for the vesicle elongation of phagophore. Disassociation of the complex takes place when the phagophore develops into a double-membrane ring known as “autophagosome”. Upon initiation of autophagy, LC3B (Atg8) is cleaved by an ubiquitin-like system i.e. cysteine protease Atg4 to produce LC3B-I, which is activated by conjugation with Atg7 in an ATP-dependent manner. Afterward, the cascade proceeds with Atg3, and Atg5-Atg12-Atg16 complex mediates the conjugation of LC3I to phosphatidylethanolamine (PE) and thus forms LC3II [84,85]. LC3-II acts as a receptor for the selection of substrates, interacting with damaged mitochondria or protein aggregates and subsequently promoting their uptake and degradation by lysosomal hydrolases [86,87] [Figure 3].

Click to view original image

Figure 3 The macroautphagy process in mammalian cells. Autophagy contributes not only to the normal but also to the pathological processes, thus it may act as a major modulator of different facets of cancer biology. Since autophagy is activated during the nutrient crisis to provide metabolites for protein synthesis and can also degrade organelles (e.g., mitochondria), aggregated proteins, and infectious agents selectively [88]. Thus, the role of autophagy is complicated, and defects in autophagy can inhibit or promote cancer [5,89].

3.1 Dual Effect of Autophagy in Cancer

A lot of studies have shown that autophagy has an important effect on several diseases. However, it is not clear whether autophagy has a pro or anti role in the diseased state [90]. In cancer, autophagy plays a dual role in promoting and stopping cancer growth. Autophagy removes damaged cells and organelles from the body in the initial and malignant phases of cancer [91]. During cancer development, autophagy acts as a protective mechanism by providing the required metabolites and energy supplies to the cells [92]. The protective roles of autophagy include the provision of nutrients during starving conditions, generation of resistance towards anticancer drugs, inhibition of various cell death mechanisms, remodeling of cellular metabolic reactions, maintaining genome integrity, etc. [93,94,95,96,97]. However, the tumor inhibitory roles of autophagy lead to cancer cell death due to increased ROS, protein aggregation and degradation of essential proteins [98,99].

Thus, autophagy has both promoting and inhibitory roles for cancer cells, which can inhibit tumor formation in early stages while can cause tumor cell survival and malignant transformation in response to various stressful triggers in later cancer stages [93,100,101].

Autophagy not only maintains the growth of healthy cells but it is also responsible for the development of various diseased conditions like neurodegeneration [102], cancer [103], type II diabetes [104] and cardiovascular diseases [105] due to its deregulation.

3.2 Epigenetic Regulation Mechanisms of Autophagy in Cancer

Multiple studies have mentioned the significant contributions of epigenetic alterations in cancer. Studies have also demonstrated that the expression of autophagy genes is regulated by epigenetic modifications in cancer cells [Table 1].

3.2.1 DNA Methylation

DNA methylation of autophagy regulatory genes has an impact on the regulation of cancer.

Hypermethylation: Hypermethyation of Ulk2 (required for autophagy initiation) causes its downregulation and autophagy disruption during the development of glioblastoma [106]. Also, hypermethylation of ATG2B, responsible for the nucleation of vesicles during autophagy, induces the growth of invasive breast cancer and ductal carcinomas. Besides this, hypermethylation of ATG4D (which has a significant regulatory role in ATG8/LC3 system) and ATG9 orthologs, also occurs in invasive ductal carcinomas [107,108]. Hypermethylation of the promoter region of ATG5 (which forms a complex with ATG12 and ATG16 during autophagy) causes its downregulation and the growth of melanoma [85,107,109]. Hypermethylation of promoter regions of autophagy regulatory elements, having tumor suppressive roles, lead to cancer promotion, for instance, hypermethylation of Beclin1 or Atg6 (which is involved in the initiation of isolation membrane formation) causes its downregulation in breast cancer cells [110,111]. Apart from this, methylation of the LC3-encoding gene i.e. MAP1LC3Av1 leads to its silencing, thereby inhibiting autophagy in normal and cancerous gastric mucosae [112]. In gastric cancer, methylation of promoter sites of the Klotho gene causes its activation which consequently leads to the enhancement of LC3-I/LC3-II expression and apoptosis in gastric cancer cells [113].

Protocadherin 17 (PCDH17), a tumor suppressor gene, increases starvation-induced autophagy and inhibits cellular proliferation in esophageal squamous cell carcinoma, colorectal cancer and gastric cancer [114,115]. It can also be silenced by the methylation of its promoter and its restoration can cause enhancement in the formation of autophagic vacuoles and upregulation of Atg-5, Atg12, and LC3B II [114]. Overexpression of tumor suppressor candidate 3 (TUSC3) occurs due to its methylation in human non-small cell lung cancer (NSCLC) cells, which inhibits cell proliferation by the induction of autophagy and apoptosis [116]. Aplasia Ras homolog member I (ARHI), a maternally imprinted tumor suppressor gene, is overexpressed and associated with breast and ovarian tumor progression by autophagic induction due to its loss of function and hypermethylation of CpG promoter elements in ARHI [117]. Ankyrin repeat and death domain containing 1A is another tumor suppressor gene whose overexpression causes inhibition of hypoxia tolerance of glioblastoma cells by damaging glucose metabolism and autophagy and is hypermethylated at its promoter region, thus is downregulated in glioblastoma [118].

Promoter methylation of B-cell translocation genes (BTG1and BTG3 in gastric cancer, BTG1 in colorectal cancer) causes aggressive and malignant cancer growth, however, BTGs have tumor-defeating roles due to their overexpression and cause inhibition of metastasis, angiogenesis, cellular proliferation and upregulation of autophagy and apoptosis [119,120,121]. BCLB (the most recently identified and the least studied Bcl-2 family member) modulates autophagy and apoptosis by acting as a starvation stress sensor. It is repressed in hepatocellular carcinoma (HCC) due to hypermethylation of the promoter region [122]. The aggressiveness and stage of cancer are associated with promoter methylation of transcription factor 21 (TCF21) due to the inhibition of autophagy in NSCLC [123].

Diminution of an enzyme nicotinamide n-methyl transferase (NNMT) causes liver carcinogenesis during metabolite depletion due to dephosphorylation of p-ULK1 activity and increased PP2A methylation leading to an increased pro-survival form of autophagy [124]. Regulation of autophagy and cancer can also occur due to the methylation of some enzymes like methylation at CpG islands of argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL) in glioblastomas. Pro-survival autophagic response can be activated initially due to exposure to PEGylated arginine deiminase (ADI-PEG20) and inhibition by chloroquine exposure increased cytotoxicity [125].

Hypomethylation/demethylation: Tumor progression can also occur due to demethylation and hypomethylation of some regulatory regions of DNA. Pro-survival form of autophagy can be activated due to the abnormal DNA demethylation of LC3A in lung adenocarcinoma [126]. The poor prognosis of ovarian tumor-initiating cells (OTICs) is due to the hypomethylation of ATG4A and histone cluster 1 H2B family member N while their DNA methylation may lead to improved patient condition [127]. Hypomethylation of the promoter region of ELFN2 (extracellular leucine rich repeat and fibronectin type III domain containing 2) leads to the activation of its tumor-promoting role by the mediation of enhanced autophagy in glioblastoma [128].

However, DNA methylation may also lead to the suppression of the oncogenic role of regulatory regions of autophagy genes. The increased methylation of endothelial PAS domain protein 1 (EPAS1) and ATG16L1 and subsequent reduction of medulloblastoma proliferation occur due to the repression of oncogenic hypoxia-inducible factor 1-alpha in medulloblastomas [128]. Thus, it can be stated that the methylation of autophagy-regulated effector molecules may affect cancer regulation substantially.

3.2.2 Histone Modifications

In cancer, histone acetylation and deacetylation are regularly occurring mechanisms, which modulate autophagy. Some of the histone modifications suppress tumors, such as the disruption of HDAC1 can cause autophagic cell death in human hepatocellular carcinoma. And HDAC6 expression deficiency can cause HCC, however, its upregulation inhibits cancer proliferation by triggering autophagic cell death in HCC [129,130]. HDAC7 is oncogenic in salivary mucoepidermoid carcinoma and thus can be used as an attractive target to overcome the problem. As reported in the literature, inhibition of HDAC7 suppressed cell growth due to the inhibition of c-Myc oncogene expression. HDAC7 inhibition also induces cell cycle arrest along with the induction of autophagy and apoptosis [131]. HDAC10 activates the pro-survival autophagy mechanism to promote cancer cell growth and protect them from cytotoxic compounds in neuroblastoma. Thus HDAC isozyme could act as a druggable target of high-grade cancer [132].

Likewise, acetylated FoxO1 has been reported to activate autophagy by binding to Atg7, thereby inducing apoptosis in human colon cancer and xenograft mouse [133]. Normally, PCAF (P300/CBP-associated factor) is found to be in a suppressed form in HCC while its upregulation in HCC causes activation of autophagy, resulting in cancer inhibition in vitro and in vivo [134]. Prostatic intraepithelial neoplasia (PIN) is caused by the reduction in autophagy due to homozygous deletion of the SIRT1 gene. Expression of androgen-responsive gene suppression and autophagy activation caused by endogenous SIRT1 in the prostate provides evidence for its tumor suppressive and checkpoint activities in the prostate and the development of PIN respectively [135]. At times, histone acetylation-regulated autophagy modulation may result in tumorigenesis, for instance, HDAC8 is highly expressed in oral squamous cell carcinoma (OSCC) however its inhibition suppressed the cancer cell growth due to the activation of apoptosis. Therefore, combination therapy with autophagy inhibitors and HDAC8 inhibitors can be a good anticancer approach in OSSC [136]. Also, epithelial-to-mesenchymal transition is linked with p62-regulated autophagy repression by maintaining the level of HDAC6 in aggressive prostate cancer [137]. Cancer cell growth is promoted by the inhibition of autophagosome maturation due to the acetylation of Atg6 by p300 at lysine 430 and 437 residues [138]. Additional, histone modification can also activate organelle-specific autophagy in cancer, for example, SIRT3 protects glioma cells against apoptotic cell death by activating mitophagy due to the association between VDAC1 and parkin [139]. Autophagy-associated cancer modulation has also been reported to be linked with methylation or de-methylation of histone. Bladder cancer growth is promoted by the overexpression of SMYD3 (a histone methyltransferase), by inducing autophagy and activating BCL2-associated transcription factor 1 (BCLAF1) expression [140]. Autophagosome formation is inhibited by histone methyltransferase (HMT) G9a (highly expressed in a wide variety of cancers), by the transcription repression of LC3 and WIPI1 [141]. Down-regulation of lysine-specific demethylase 2B (a JHDM family member, commonly expressed in gastric cancer and acts as a histone lysine demethylase), inhibits cancer cell proliferation in vitro and gastric cancer xenograft model by the activation of autophagy [142]. However, inhibition of lysine-specific demethylase 4A may inhibit glioma cell survival by autophagy activation and thus, it can be used as a promising marker for combating aggressive gliomas [143]. Proliferation of neuroblastoma cells can be suppressed by the inhibition of G9a, an H3K9 methyltransferase, by autophagy activation due to the up-regulation of autophagy genes and LC3B expression [144]. Activation of Beclin-1 leads to autophagy activation due to the inhibition of euchromatic histone-lysine N-methyltransferase 2, which in turn prevents cancer cell growth in breast cancer [145]. Thus, histone modification levels in autophagy regulation may affect tumor regulation significantly.

3.2.3 Micro RNAs

A lot of miRNAs that modulate autophagy also have growth inhibitory effects in cancer cells, such as in breast cancer cells, the tumor-inhibition by miR-101 is due to the basal and rapamycin-induced autophagy repression by affecting RAB5A, STMN1, and ATG4D [146]. It has been reported that miR-30a inhibits Beclin-1 expression by binding to the 3’-UTR, which in turn leads to autophagy and tumor cell growth inhibition in medulloblastoma cells [74,147]. miR-30d inhibits autophagy by targeting pPI3-K, Beclin-1 and Atg5 in colon carcinoma which also abrogates growth and promotes apoptosis [148]. miR-372 has a tumor-suppressing role by lowering the expression of ULK1 and autophagy in human pancreatic adenocarcinomas [149]. miR-130a lowers the expression of ATG2B and DICER1 in chronic lymphocytic leukemia and also inhibits autophagy by suppressing autophagosomal formation and inducing apoptosis [150]. miR-204 (a von Hippel-Lindau (VHL)-regulated tumor suppressor) is known to suppress cancer cell proliferation by inhibiting LC3B-mediated autophagy in renal clear cell carcinoma [151]. miR-375 negatively affects the viability of hepatocellular carcinoma cells by inhibiting autophagy under hypoxic conditions due to the suppression of ATG7 [152]. In NSCLC, miR-143 inhibited cancer cell growth through the down-regulation of autophagy gene ATG2B at mRNA and protein levels [153]. Overexpression of a few tumor-inhibitory miRNAs which have less expression in cancers may inhibit cancer cell growth. Restoration of downregulated miR-340 in glioma cells can cause cell growth suppression and induces cell-cycle arrest, autophagy, and apoptosis [154]. In human glioblastoma, the overexpression of miR224-3p suppresses the precursor form of autophagy in hypoxic conditions by targeting ATG5 and FIP200 [155]. YY1 is found to promote SQSTM1 expression, which subsequently activates autophagy by the inhibition of miR-372 expression epigenetically, whereas high expression of miR-372 inhibits the protective effects of autophagy in breast cancer in vivo [156]. Colon cancer is suppressed by miR-18a through the induction of apoptosis via autophagic degradation of heterogeneous nuclear ribonucleoprotein A1 [157]. In the same way, miR-107 inhibits tumor growth, cellular proliferation and migration due to the regulation of high mobility group protein B1 (HMGB1) by autophagy repression in breast cancer [158]. In cervical and lung cancer, miR7-3HG/mir-7 lowers the expression of AMBRA1 at mRNA and protein levels by targeting the 3’UTR region of AMBRA1 and consequently affects oncogenesis by inhibiting autophagy [159]. The association of onco-miRNA with autophagy genes also has oncogenic properties. In NSCLC, overexpression of miR-18a-5p causes tumorigenesis by targeting interferon regulatory factor 2 (IRF2) and inhibiting cell proliferation through apoptosis and protective autophagy [160]. In esophageal squamous cell carcinoma and breast cancer, oncogenic miR-638 promotes malignant tumor growth by targeting tumor-suppressor DACT3 and promoting autophagy [161]. Similarly, miR-638 suppresses autophagy, promotes melanoma growth by increasing metastasis and expression of the transcriptional repressor TFAP2A/AP2α [162]. miR-30e which inhibits autophagy by targeting 3’UTR of ATG5, is inhibited by DIM (3, 3’-diindolylmethane), an indole derivative, which in turn leads to the suppression of gastric cancer cell proliferation [163]. Likewise, UVRAG-induced autophagy and apoptosis are regulated by miR-183 in colorectal cancer, and inhibition of miR-183 suppresses in vivo cancer growth in the HT-29 xenograft model [164]. In laryngeal carcinoma, cancer cell growth is inhibited by autophagy induction due to suppression of miR-26b [165]. In glioma cells, overexpression of p72 promotes invasion and migration by inhibiting the Beclin-1 gene due to up-regulation of miR-5195-3p and miR-34-5p [166]. In melanoma, autophagic cell death (due to glucose deprivation through down-regulation Atg7 and ULK1) is inhibited by miR-290-295 cluster [167]. MiR-20a mediates breast oncogenesis by inhibiting autophagy and instability in target proteins, such as BECLIN-1, SQSTM1 and ATG16L1 [168]. Thus onco-miRNAs as well as tumor-suppressive miRNAs have regulatory effects on autophagy and may significantly affect tumor regulation.

Table 1 Role of epigenetic modifications in cancer-related autophagy and associated proteins.

4. Epigenetic Modifications of Autophagy and Therapeutic Response

It is noteworthy that bioactive constituents of plants have the ability to inhibit cancer at all stages including initiation, promotion, and progression [179]. Many anticancer natural products have been reported to have the ability to regulate gene expression through epigenetic mechanisms [Table 2] [180]. A great range of plant-based compounds have gene expression modulation ability through epigenetic pathways [181] and thus can be used as therapeutics due to their potential to regulate autophagy pathways in cancer models in vitro or in vivo [182]. For instance, polyphenols are the most common naturally bioactive compounds found in fruits, seeds, vegetables, and nuts [183]. Several polyphenols (resveratrol, curcumin) can also affect numerous cell targets that can induce or inhibit autophagy. Autophagy modulation occurs due to epigenetic changes and thus can be profoundly investigated further.

Table 2 Bioactive dietary compounds and their sources.

Scientists all over the world are becoming more and more interested in the biological and clinical effects of epigenetic changes in cancer autophagy. Most of the literature on epigenetic modifications of autophagy contributes to cancer diagnosis and treatment. Epigenetic modifications are potentially reversible and can be restored to normal state by therapeutic approaches, as such, these are considered hallmarks to study cancer and designing next- generation cancer therapies [196]. Besides natural products, some other therapeutic molecules that can modulate autophagy through epigenetic modification are listed in Table 3.

Table 3 Effects of some epigenetic drugs on autophagy in cancer cells.

Clinical trials of epigenetic therapy in cancers: several epigenetic inhibitors are under development or in ongoing clinical trials. The present epigenetic therapy mainly involves agents of DNA methylation and histone modification. We summarize the current clinical trials of epigenetic therapy for different cancers [Table 4].

Table 4 Clinical trials of epigenetic therapy in cancer patients (clinicaltrials.gov).

Nevertheless, it has not been experimentally proven yet that the bioactive constituents with cancer-inhibitory properties can modulate autophagy via epigenetics. However, the experimental validation in this aspect may vary depending on the cell type and target proteins.

5. Conclusions

Epigenetic modifications like DNA methylation, histone modification, and miRNAs may directly or indirectly impact autophagy. In cancer, epigenetically regulated autophagy is majorly involved in tumorigenesis, metastasis, and drug resistance. Thus, potent biomarkers of cancer can be identified with the help of a deeper understanding of epigenetic modification of autophagy. However, the role of autophagy in human diseases is still difficult to understand while the mutations associated with epigenetics generate carcinogenic signals to promote cancer.

Finally, epigenetic regulation of autophagy is precise and depends widely on different stages and types of tumors. Various epigenetic modifications have been reported to affect and modulate the expression of autophagy genes. Some epigenetic regulators have been detected to be involved in autophagy and have also been confirmed as potential targets for antitumor therapy. Due to technological and pharmacochemistry progress in the past decade, different methods have been developed to identify selective, small molecule inhibitors of the enzymes associated with epigenetics modifications. Inhibition of these enzymes may trigger protective or lethal autophagy. Conclusively, the above information gives a new insight into the molecular mechanism of epigenetic modulation of autophagy in cancer.

Acknowledgments

We would like to thank the Hon’ble Vice-Chancellor, Integral University, Lucknow for the necessary infrastructure support and Dean Office, R&D, Integral University for providing manuscript communication number (IU/R&D/2022-MCN0001510).

Author Contributions

SP: Conceptualization, Writing - original draft, Writing - review & editing; SFR: writing – Review & Editing; AH: writing – Review & Editing; UA: writing – Review & Editing; SSM: conceptualization, Supervision, Writing - original draft, Writing - review & editing, Critical revision of the article. All authors contributed to the article and approved the submitted version.

Funding

No specific funding was available for this work.

Competing Interests

Authors have no conflict of interest.

References

  1. World Health Organization Cancer. [Internet]. Geneva, Switzerland: World Health Organization; 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer.
  2. Sawyers C. Targeted cancer therapy. Nature. 2004; 432: 294-297. [CrossRef]
  3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68: 394-424. [CrossRef]
  4. Pritchard JR, Lauffenburger DA, Hemann MT. Understanding resistance to combination chemotherapy. Drug Resist Updat. 2012; 15: 249-257. [CrossRef]
  5. Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev. 2011; 25: 1999-2010. [CrossRef]
  6. Sui X, Zhu J, Zhou J, Wang X, Li D, Han W, et al. Epigenetic modifications as regulatory elements of autophagy in cancer. Cancer lett. 2015; 360: 106-113. [CrossRef]
  7. Hervouet E, Claude-Taupin A, Gauthier T, Perez V, Fraichard A, Adami P, et al. The autophagy GABARAPL1 gene is epigenetically regulated in breast cancer models. BMC Cancer. 2015; 15: 1-13. [CrossRef]
  8. Hasan A, Haque E, Hameed R, Maier PN, Irfan S, Kamil M, et al. Hsp90 inhibitor gedunin causes apoptosis in A549 lung cancer cells by disrupting Hsp90: Beclin-1: Bcl-2 interaction and downregulating autophagy. Life Sci. 2020; 256: 118000. [CrossRef]
  9. Bollati V, Baccarelli A. Environmental epigenetics. Heredity. 2010; 105: 105-112. [CrossRef]
  10. Gerhauser C. Cancer chemoprevention and nutri-epigenetics: State of the art and future challenges. In: Natural products in cancer prevention and therapy. Berlin: Springer-Verlag Berlin Heidelberg; 2012. pp. 73-132. doi: 10.1007/128-2012-360. [CrossRef]
  11. Thakur SV, Deb G, Babcook MA, Gupta S. Plant phytochemicals as epigenetic modulators: Role in cancer chemoprevention. AAPS J. 2014; 16: 151-163. doi: 10.1208/s12248-013-9548-5. [CrossRef]
  12. Lipps HJ, Postberg J, Jackson DA, Hajji N, Joseph B. Epigenetic regulation of cell life and death decisions and deregulation in cancer. Essays Biochem. 2010; 48: 121-146. doi:10.1042/BSE0480121. [CrossRef]
  13. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019; 4: 62. doi:10.1038/s41392-019-0095-0. [CrossRef]
  14. Wiman KG, Zhivotovsky B. Understanding cell cycle and cell death regulation provides novel weapons against human diseases. J Intern Med. 2017; 281: 483-495. doi:10.1111/joim.12609. [CrossRef]
  15. Skourti E, Dhillon P. Cancer epigenetics: Promises and pitfalls for cancer therapy. FEBS J. 2022; 289: 1156-1159. [CrossRef]
  16. Ali M, Hanif M, Farooqi AA. Epigenetic therapy for cancer. Pak J Pharm Sci. 2015; 28: 1023-1032.
  17. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983; 301: 89-92. [CrossRef]
  18. Ryan J, Wrigglesworth J, Loong J, Fransquet PD, Woods RL. A systematic review and meta-analysis of environmental, lifestyle, and health factors associated with DNA methylation age. J Gerontol. 2020; 75: 481-494. [CrossRef]
  19. Bhol CS, Panigrahi DP, Praharaj PP, Mahapatra KK, Patra S, Mishra SR, et al. Epigenetic modifications of autophagy in cancer and cancer therapeutics. Semin Cancer Biol. 2020; 66: 22-33. [CrossRef]
  20. Robertson KD. DNA methylation and human disease. Nat Rev Genet. 2005; 6: 597-610. [CrossRef]
  21. Lea AJ, Vockley CM, Johnston RA, Del Carpio CA, Barreiro LB, Reddy TE, et al. Genome-wide quantification of the effects of DNA methylation on human gene regulation. ELife. 2018; 7: e37513. [CrossRef]
  22. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013; 38: 23-38. [CrossRef]
  23. Brown R, Strathdee G. Epigenomics and epigenetic therapy of cancer. Trends Mol Med. 2002; 8: S43-S48. [CrossRef]
  24. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004; 22: 4632-4642. [CrossRef]
  25. Momparler RL. Cancer epigenetics. Oncogene. 2003; 22: 6479- 6483. [CrossRef]
  26. Robertson KD, Jones PA. DNA methylation: Past, present and future directions. Carcinogenesis. 2000; 21: 461-467. [CrossRef]
  27. Szyf M, Pakneshan P, Rabbani SA. DNA methylation and breast cancer. Biochem Pharmacol. 2004; 68: 1187-1197. [CrossRef]
  28. Wang YM, Wang R, Wen DG, Li Y, Guo W, Wang N, et al. Single nucleotide polymorphism in DNA methyltransferase 3B promoter and its association with gastric cardiac adenocarcinoma in North China. World J Gastroenterol. 2005; 11: 3623-3627. [CrossRef]
  29. Luczak MW, Jagodziński PP. The role of DNA methylation in cancer development. Folia Histochem Cytobiol. 2006; 44: 143-154.
  30. Joo JE, Dowty JG, Milne RL, Wong EM, Dugué PA, English D, et al. Heritable DNA methylation marks associated with susceptibility to breast cancer. Nat Commun. 2018; 9: 1-12. [CrossRef]
  31. Cui H, Hu Y, Guo D, Zhang A, Gu Y, Zhang S, et al. DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer. Oncogene. 2018; 37: 4358-4371. [CrossRef]
  32. Bormann F, Rodríguez-Paredes M, Lasitschka F, Edelmann D, Musch T, Benner A, et al. Cell-of-origin DNA methylation signatures are maintained during colorectal carcinogenesis. Cell Rep. 2018; 23: 3407-3418. [CrossRef]
  33. Liu T, Wu X, Chen T, Luo Z, Hu X. Downregulation of DNMT3A by miR-708-5p Inhibits Lung Cancer Stem Cell–like Phenotypes through Repressing Wnt/β-catenin SignalingmiR-708-5p Inhibits Lung Cancer Stemness. Clin Cancer Res. 2018; 24: 1748-1760. [CrossRef]
  34. Xiong Z, Ren S, Chen H, Liu Y, Huang C, Zhang YL, et al. PAX9 regulates squamous cell differentiation and carcinogenesis in the oro‐oesophageal epithelium. J Pathol. 2018; 244: 164-175. [CrossRef]
  35. Arechederra M, Daian F, Yim A, Bazai SK, Richelme S, Dono R, et al. Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat Commun. 2018; 9: 1-16. [CrossRef]
  36. Li J, Wu X, Zhou Y, Lee M, Guo L, Han W, et al. Decoding the dynamic DNA methylation and hydroxymethylation landscapes in endodermal lineage intermediates during pancreatic differentiation of hESC. Nucleic Acids Res. 2018; 46: 2883-2900. [CrossRef]
  37. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003; 349: 2042-2054. [CrossRef]
  38. Michalowski MB, Plantaz D. Pediatric ependymomas: Role of methylation. Pediatr Cancer. 2013; 4: 295-300. [CrossRef]
  39. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002; 99: 3740-3745. [CrossRef]
  40. Wang Y, Leung FC. An evaluation of new criteria for CpG islands in the human genome as gene markers. Bioinformatics. 2004; 20: 1170-1177. [CrossRef]
  41. Bird A. The essentials of DNA methylation. Cell. 1992; 70: 5-8. [CrossRef]
  42. Esteller M. Epigenetics in cancer. N Engl J Med. 2008; 358: 1148-1159. [CrossRef]
  43. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, et al. The human colon cancer methylome shows similar hypo-and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009; 41: 178-186. [CrossRef]
  44. Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R, et al. Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet. 2009; 41: 1350-1353. [CrossRef]
  45. Feinberg AP, Vogelstein B, Droller MJ, Baylin SB, Nelkin BD. Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer. Science. 1983; 220: 1175-1177. [CrossRef]
  46. Kulis M, Esteller M. DNA methylation and cancer. Adv Genet. 2010; 70: 27-56. [CrossRef]
  47. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003; 300: 455. [CrossRef]
  48. Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 2006; 66: 8462-9468. [CrossRef]
  49. Fraga MF, Herranz M, Espada J, Ballestar E, Paz MF, Ropero S, et al. A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 2004; 64: 5527-5534. [CrossRef]
  50. Lim DH, Maher ER. Genomic imprinting syndromes and cancer. Adv Genet. 2010; 70: 145-175. [CrossRef]
  51. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell. 1999; 98: 285-294. [CrossRef]
  52. Lusser A, Kadonaga JT. Chromatin remodeling by ATP-dependent molecular machines. Bioessays. 2003; 25: 1192-1200. [CrossRef]
  53. Martens JA, Winston F. Recent advances in understanding chromatin remodeling by Swi/Snf complexes. Curr Opin Genet Dev. 2003; 13: 136-142. [CrossRef]
  54. Davis PK, Brackmann RK. Chromatin remodeling and cancer. Cancer Biol Ther. 2003; 2: 22-29. [CrossRef]
  55. Grunstein M. Yeast heterochromatin: Regulation of its assembly and inheritance by histones. Cell. 1998; 93: 325-328. [CrossRef]
  56. Cho KS, Elizondo LI, Boerkoel CF. Advances in chromatin remodeling and human disease. Curr Opin Genet Dev. 2004; 14: 308-315. [CrossRef]
  57. Kim TH, Barrera LO, Zheng M, Qu C, Singer MA, Richmond TA, et al. A high-resolution map of active promoters in the human genome. Nature. 2005; 436: 876-880. [CrossRef]
  58. Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018; 378: 1323-1334. [CrossRef]
  59. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000; 403: 41-45. [CrossRef]
  60. Costa FF. Epigenomics in cancer management. Cancer Manag Res. 2010; 2: 255-265. [CrossRef]
  61. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rausche FJ. SETDB1: A novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 2002; 16: 919-932. [CrossRef]
  62. Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harb Perspect Biol. 2016; 8: a019521. [CrossRef]
  63. Zhao Z, Shilatifard A. Epigenetic modifications of histones in cancer. Genome Biol. 2019; 20: 245. [CrossRef]
  64. Marmorstein R, Zhou MM. Writers and readers of histone acetylation: Structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol. 2014; 6: a018762. [CrossRef]
  65. Seto E, Yoshida M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014; 6: a018713. [CrossRef]
  66. Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009; 138: 1019-1031. [CrossRef]
  67. Eissenberg JC, Shilatifard A. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol. 2010; 339: 240-249. [CrossRef]
  68. Nowak SJ, Corces VG. Phosphorylation of histone H3: A balancing act between chromosome condensation and transcriptional activation. Trends Genet. 2004; 20: 214-220. [CrossRef]
  69. Gomes AQ, Nolasco S, Soares H. Non-coding RNAs: Multi-tasking molecules in the cell. Int J Mol Sci. 2013; 14: 16010-16039. [CrossRef]
  70. Hong J, Zhang H, Kawase-Koga Y, Sun T. MicroRNA function is required for neurite outgrowth of mature neurons in the mouse postnatal cerebral cortex. Front Cell Neurosci. 2013; 7: 151. [CrossRef]
  71. Li PF, Chen SC, Xia T, Jiang XM, Shao YF, Xiao BX, et al. Non-coding RNAs and gastric cancer. World J Gastroenterol. 2014; 20: 5411. [CrossRef]
  72. Ferreira HJ, Esteller M. Non-coding RNAs, epigenetics, and cancer: Tying it all together. Cancer Metastasis Rev. 2018; 37: 55-73. [CrossRef]
  73. Bracken CP, Szubert JM, Mercer TR, Dinger ME, Thomson DW, Mattick JS, et al. Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA-independent endonucleolytic cleavage. Nucleic Acids Res. 2011; 39: 5658-5668. [CrossRef]
  74. Singh SV, Dakhole AN, Deogharkar A, Kazi S, Kshirsagar R, Goel A, et al. Restoration of miR-30a expression inhibits growth, tumorigenicity of medulloblastoma cells accompanied by autophagy inhibition. Biochem Biophys Res Commun. 2017; 491: 946-952. [CrossRef]
  75. Wang B, Li D, Kovalchuk I, Apel IJ, Chinnaiyan AM, Wóycicki RK, et al. miR-34a directly targets tRNAiMet precursors and affects cellular proliferation, cell cycle, and apoptosis. Proc Natl Acad Sci. 2018; 115: 7392-7397. [CrossRef]
  76. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007; 302: 1-12. [CrossRef]
  77. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci. 2004; 101: 2999-3004. [CrossRef]
  78. Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. Biochim Biophys Acta Rev Cancer. 2016; 1865: 275-288. [CrossRef]
  79. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010; 140: 313-326. [CrossRef]
  80. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med. 2003; 9: 65-76. doi: 10.1007/BF03402040. [CrossRef]
  81. Cuervo AM. Autophagy: Many paths to the same end. Mol Cell Biochem. 2004; 263: 55-72. [CrossRef]
  82. Kelekar A. Autophagy. Ann N Y Acad Sci. 2006; 1066: 259-271. [CrossRef]
  83. Mizushima N. A brief history of autophagy from cell biology to physiology and disease. Nat Cell Biol. 2018; 20: 521-527. [CrossRef]
  84. Grumati P, Dikic I. Ubiquitin signaling and autophagy. J Biol Chem. 2018; 293: 5404-5413. [CrossRef]
  85. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, et al. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem. 2007; 282: 37298-37302. [CrossRef]
  86. Cohen-Kaplan V, Livneh I, Avni N, Fabre B, Ziv T, Kwon YT, et al. p62-and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc Natl Acad Sci. 2016; 113: E7490-9. [CrossRef]
  87. Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018; 20: 233-242. [CrossRef]
  88. Peixoto P, Grandvallet C, Feugeas JP, Guittaut M, Hervouet E. Epigenetic control of autophagy in cancer cells: A key process for cancer-related phenotypes. Cells. 2019; 8: 1656. [CrossRef]
  89. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature. 2010; 466: 68-76. [CrossRef]
  90. Saha S, Panigrahi DP, Patil S, Bhutia SK. Autophagy in health and disease: A comprehensive review. Biomed Pharmacother. 2018; 104: 485-495. [CrossRef]
  91. Cordani M, Butera G, Pacchiana R, Donadelli M. Molecular interplay between mutant p53 proteins and autophagy in cancer cells. Biochim Biophys Acta (BBA) Bioenerg. 2017; 1867: 19-28. [CrossRef]
  92. Liao JK, Zhou B, Zhuang XM, Zhuang PL, Zhang DM, Chen WL. Cancer-associated fibroblasts confer cisplatin resistance of tongue cancer via autophagy activation. Biomed Pharmacother. 2018; 97: 1341-1348. [CrossRef]
  93. Poillet-Perez L, Xie X, Zhan LE, Yang Y, Sharp DW, Hu ZS, et al. Autophagy maintains tumour growth through circulating arginine. Nature. 2018; 563: 569-573. [CrossRef]
  94. Polishchuk EV, Merolla A, Lichtmannegger J, Romano A, Indrieri A, Ilyechova EY, et al. Activation of autophagy, observed in liver tissues from patients with Wilson disease and from ATP7B-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology. 2019; 156: 1173-1189. [CrossRef]
  95. Debnath J. Detachment-induced autophagy during anoikis and lumen formation in epithelial acini. Autophagy. 2008; 4: 351-353. [CrossRef]
  96. Talukdar S, Pradhan AK, Bhoopathi P, Shen XN, August LA, Windle JJ, et al. MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells. Proc Natl Acad Sci. 2018; 115: 5768-5773. [CrossRef]
  97. Yang Z, Sun Q, Guo J, Wang S, Song G, Liu W, et al. GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells. Autophagy. 2019; 15: 668-685. [CrossRef]
  98. Joshi A, Iyengar R, Joo JH, Li-Harms XJ, Wright C, Marino R, et al. Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1. Cell Death Differ. 2016; 23: 216-230. [CrossRef]
  99. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009; 137: 1062-1075. [CrossRef]
  100. Galluzzi L, Pietrocola F, Bravo‐San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015; 34: 856-880. [CrossRef]
  101. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci. 2003; 100: 15077-15082. [CrossRef]
  102. Guo F, Liu X, Cai H, Le W. Autophagy in neurodegenerative diseases: Pathogenesis and therapy. Brain Pathol. 2018; 28: 3-13. [CrossRef]
  103. Yun CW, Lee SH. The roles of autophagy in cancer. Int J Mol Sci. 2018; 19: 3466. [CrossRef]
  104. Sarparanta J, García-Macia M, Singh R. Autophagy and mitochondria in obesity and type 2 diabetes. Curr Diabetes Rev. 2017; 13: 352-369. [CrossRef]
  105. Mialet-Perez J, Vindis C. Autophagy in health and disease: Focus on the cardiovascular system. Essays Biochem. 2017; 61: 721-732. [CrossRef]
  106. Shukla S, Patric IR, Patil V, Shwetha SD, Hegde AS, Chandramouli BA, et al. Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth. J Biol Chem. 2014; 289: 22306-22318. [CrossRef]
  107. Yamaguchi J, Suzuki C, Nanao T, Kakuta S, Ozawa K, Tanida I, et al. Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis. Autophagy. 2018; 14: 764-777. [CrossRef]
  108. Zhang X, Li C, Wang D, Chen Q, Li CL, Li HJ. Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma. Gene. 2016; 590: 285-292. [CrossRef]
  109. Liu H, He Z, von Rütte T, Yousefi S, Hunger RE, Simon HU. Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med. 2013; 5: 202ra123. [CrossRef]
  110. Wu CL, Zhang SM, Lin L, Gao SS, Fu KF, Liu XD, et al. BECN1-knockout impairs tumor growth, migration and invasion by suppressing the cell cycle and partially suppressing the epithelial-mesenchymal transition of human triple-negative breast cancer cells. Int J Oncol. 2018; 53: 1301-1312. [CrossRef]
  111. Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer. 2010; 10: 1-12. [CrossRef]
  112. Muhammad JS, Nanjo S, Ando T, Yamashita S, Maekita T, Ushijima T, et al. Autophagy impairment by H elicobacter pylori‐induced methylation silencing of MAP1LC3Av1 promotes gastric carcinogenesis. Int J Cancer Res. 2017; 140: 2272-2283. [CrossRef]
  113. Xie B, Zhou J, Shu G, Liu DC, Zhou J, Chen J, et al. Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: Tumor suppressive role of klotho in gastric cancer. Cancer Cell Int. 2013; 13: 1-10. [CrossRef]
  114. Hu X, Sui X, Li L, Huang X, Rong R, Su X, et al. Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 2013; 229: 62-73. [CrossRef]
  115. Haruki S, Imoto I, Kozaki KI, Matsui T, Kawachi H, Komatsu S, et al. Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma. Carcinogenesis. 2010; 31: 1027-1036. [CrossRef]
  116. Peng Y, Cao J, Yao XY, Wang JX, Zhong MZ, Gan PP, et al. TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/β-catenin signaling. Oncotarget. 2017; 8: 52960. [CrossRef]
  117. Yu Y, Luo R, Lu Z, Feng WW, Badgwell D, Issa JP, et al. Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Meth Enzymol. 2006; 407: 455-468. [CrossRef]
  118. Feng J, Zhang Y, She X, Sun Y, Fan L, Ren X, et al. Hypermethylated gene ANKDD1A is a candidate tumor suppressor that interacts with FIH1 and decreases HIF1α stability to inhibit cell autophagy in the glioblastoma multiforme hypoxia microenvironment. Oncogene. 2019; 38: 103-119. [CrossRef]
  119. Zheng HC, Li J, Shen DF, Yang XF, Zhao S, Wu YZ, et al. BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: A potential target for gene therapy. Oncotarget. 2015; 6: 19685. [CrossRef]
  120. Gou WF, Yang XF, Shen DF, Zhao S, Liu YP, Sun HZ, et al. The roles of BTG3 expression in gastric cancer: A potential marker for carcinogenesis and a target molecule for gene therapy. Oncotarget. 2015; 6: 19841. [CrossRef]
  121. Zhao S, Chen SR, Yang XF, Shen DF, Takano Y, Su RJ, et al. BTG1 might be employed as a biomarker for carcinogenesis and a target for gene therapy in colorectal cancers. Oncotarget. 2017; 8: 7502. [CrossRef]
  122. Liu X, Hu X, Kuang Y, Yan P, Li L, Li C, et al. BCLB, methylated in hepatocellular carcinoma, is a starvation stress sensor that induces apoptosis and autophagy through the AMPK-mTOR signaling cascade. Cancer Lett. 2017; 395: 63-71. [CrossRef]
  123. Chen B, Zeng C, Ye Y, Wu D, Mu Z, Liu J, et al. Promoter methylation of TCF21 may repress autophagy in the progression of lung cancer. J Cell Commun Signal. 2018; 12: 423-432. [CrossRef]
  124. Shin JH, Park CW, Yoon G, Hong SM, Choi KY. NNMT depletion contributes to liver cancer cell survival by enhancing autophagy under nutrient starvation. Oncogenesis. 2018; 7: 1-14. [CrossRef]
  125. Syed N, Langer J, Janczar K, Singh P, Lo Nigro C, Lattanzio L, et al. Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death Dis. 2013; 4: e458. [CrossRef]
  126. Nihira K, Miki Y, Iida S, Narumi S, Ono K, Iwabuchi E, et al. An activation of LC3A‐mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma. J Pathol. 2014; 234: 277-288. [CrossRef]
  127. Liao YP, Chen LY, Huang RL, Su PH, Chan MW, Chang CC, et al. Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients. Hum Mol Genet. 2014; 23: 1894-1906. [CrossRef]
  128. Liu C, Fu H, Liu X, Lei Q, Zhang Y, She X, et al. LINC00470 coordinates the epigenetic regulation of ELFN2 to distract GBM cell autophagy. Mol Ther. 2018; 26: 2267-2281. [CrossRef]
  129. Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Chang YG, et al. Histone deacetylase 6 functions as a tumor suppressor by activating c‐Jun NH2‐terminal kinase‐mediated beclin 1‐dependent autophagic cell death in liver cancer. Hepatology. 2012; 56: 644-657. [CrossRef]
  130. Xie HJ, Noh JH, Kim JK, Jung KH, Eun JW, Bae HJ, et al. HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer. PloS One. 2012; 7: e34265. [CrossRef]
  131. Ahn MY, Yoon JH. Histone deacetylase 7 silencing induces apoptosis and autophagy in salivary mucoepidermoid carcinoma cells. J Oral Pathol Med. 2017; 46: 276-283. [CrossRef]
  132. Oehme I, Linke JP, Böck BC, Milde T, Lodrini M, Hartenstein B, et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Pro Natl Acad Sci. 2013; 110: E2592- E2601. [CrossRef]
  133. Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol. 2010; 12: 665-675. [CrossRef]
  134. Jia YL, Xu M, Dou CW, Liu ZK, Xue YM, Yao BW, et al. P300/CBP-associated factor (PCAF) inhibits the growth of hepatocellular carcinoma by promoting cell autophagy. Cell Death Dis. 2016; 7: e2400. [CrossRef]
  135. Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, et al. Disruption of a sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formationsirt1 governs autophagy and pin formation. Cancer Res. 2011; 71: 964-975. [CrossRef]
  136. Ahn MY, Yoon JH. Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma. Oncol Rep. 2017; 37: 540-546. [CrossRef]
  137. Jiang X, Huang Y, Liang X, Jiang F, He Y, Li T, et al. Metastatic prostate cancer‐associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6. Prostate. 2018; 78: 426-434. [CrossRef]
  138. Sun T, Li X, Zhang P, Chen WD, Zhang HL, Li DD, et al. Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. Nat commun. 2015; 6: 1-12. [CrossRef]
  139. Qiao A, Wang K, Yuan Y, Guan Y, Ren X, Li L, et al. Correction: Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia. Oncotarget. 2018; 9: 27318. [CrossRef]
  140. Shen B, Tan M, Mu X, Qin Y, Zhang F, Liu Y, et al. Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy. Tumor Biol. 2016; 37: 7371-7381. [CrossRef]
  141. Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA, et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013; 33: 3983-3993. [CrossRef]
  142. Zhao E, Tang C, Jiang X, Weng X, Zhong X, Zhang D, et al. Inhibition of cell proliferation and induction of autophagy by KDM2B/FBXL10 knockdown in gastric cancer cells. Cell Signal. 2017; 36: 222-229. [CrossRef]
  143. Wang B, Fan X, Ma C, Lei H, Long Q, Chai Y. Downregulation of KDM4A suppresses the survival of glioma cells by promoting autophagy. J Mol Neurosci. 2016; 60: 137-144. [CrossRef]
  144. Ke XX, Zhang D, Zhu S, Xia Q, Xiang Z, Cui H. Correction: Inhibition of H3K9 methyltransferase G9a repressed cell proliferation and induced autophagy in neuroblastoma cells. PloS One. 2019; 14: e0213135. [CrossRef]
  145. Park SE, Yi HJ, Suh N, Park YY, Koh JY, Jeong SY, et al. Correction: Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB. Oncotarget. 2019; 10: 4348. [CrossRef]
  146. Frankel LB, Wen J, Lees M, Hoyer‐Hansen M, Farkas T, Krogh A, et al. microRNA‐101 is a potent inhibitor of autophagy. EMBO J. 2011; 30: 4628-4641. [CrossRef]
  147. Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, et al. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy. 2009; 5: 816-823. [CrossRef]
  148. Zhang R, Xu J, Zhao J, Bai J. Mir-30d suppresses cell proliferation of colon cancer cells by inhibiting cell autophagy and promoting cell apoptosis. Tumor Biol. 2017; 39: 1010428317703984. [CrossRef]
  149. Chen H, Zhang Z, Lu Y, Song K, Liu X, Xia F, et al. Downregulation of ULK 1 by micro RNA‐372 inhibits the survival of human pancreatic adenocarcinoma cells. Cancer Sci. 2017; 108: 1811-1819. [CrossRef]
  150. Kovaleva V, Mora R, Park YJ, Plass C, Chiramel AI, Bartenschlager R, et al. miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells. Cancer Res. 2012; 72: 1763-1772. [CrossRef]
  151. Mikhaylova O, Stratton Y, Hall D, Kellner E, Ehmer B, Drew AF, et al. VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell. 2012; 21: 532-546. [CrossRef]
  152. Chang Y, Yan W, He X, Zhang L, Li C, Huang H, et al. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 2012; 143: 177-187. [CrossRef]
  153. Wei J, Ma Z, Li Y, Zhao B, Wang D, Jin Y, et al. miR‑143 inhibits cell proliferation by targeting autophagy‑related 2B in non‑small cell lung cancer H1299 cells. Mol Med Rep. 2015; 11: 571-576. [CrossRef]
  154. Huang D, Qiu S, Ge R, He L, Li M, Li Y, et al. miR-340 suppresses glioblastoma multiforme. Oncotarget. 2015; 6: 9257. [CrossRef]
  155. Guo X, Xue H, Guo X, Gao X, Xu S, Yan S, et al. MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells. Oncotarget. 2015; 6: 41620. [CrossRef]
  156. Feng L, Ma Y, Sun J, Shen Q, Liu L, Lu H, et al. YY1-MIR372-SQSTM1 regulatory axis in autophagy. Autophagy. 2014; 10: 1442-1453. [CrossRef]
  157. Fujiya M, Konishi H, Mohamed Kamel MK, Ueno N, Inaba Y, Moriichi K, et al. microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1. Oncogene. 2014; 33: 4847-4856. [CrossRef]
  158. Ai H, Zhou W, Wang Z, Qiong G, Chen Z, Deng S. microRNAs‐107 inhibited autophagy, proliferation, and migration of breast cancer cells by targeting HMGB1. J Cell Biochem. 2019; 120: 8696-8705. [CrossRef]
  159. Capizzi M, Strappazzon F, Cianfanelli V, Papaleo E, Cecconi F. MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1. Autophagy. 2017; 13: 554-566. [CrossRef]
  160. Liang C, Zhang X, Wang HM, Liu XM, Zhang XJ, Zheng B, et al. MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer. Cell Death Dis. 2017; 8: e2764. [CrossRef]
  161. Ren Y, Chen Y, Liang X, Lu Y, Pan W, Yang M. MiRNA-638 promotes autophagy and malignant phenotypes of cancer cells via directly suppressing DACT3. Cancer Lett. 2017; 390: 126-136. [CrossRef]
  162. Bhattacharya A, Schmitz U, Raatz Y, Schönherr M, Kottek T, Schauer M, et al. miR-638 promotes melanoma metastasis and protects melanoma cells from apoptosis and autophagy. Oncotarget. 2015; 6: 2966. [CrossRef]
  163. Ye Y, Fang Y, Xu W, Wang Q, Zhou J, Lu R. 3, 3′-Diindolylmethane induces anti-human gastric cancer cells by the miR-30e-ATG5 modulating autophagy. Biochem Pharmacol. 2016; 115: 77-84. [CrossRef]
  164. Huangfu L, Liang H, Wang G, Su X, Li L, Du Z, et al. miR-183 regulates autophagy and apoptosis in colorectal cancer through targeting of UVRAG. Oncotarget. 2016; 7: 4735. [CrossRef]
  165. Wang S, Guo D, Li C. Downregulation of miRNA-26b inhibits cancer proliferation of laryngeal carcinoma through autophagy by targeting ULK2 and inactivation of the PTEN/AKT pathway. Oncol Rep. 2017; 38: 1679-1687. [CrossRef]
  166. Zhang Z, Tian H, Miao Y, Feng X, Li Y, Wang H, et al. Upregulation of p72 enhances malignant migration and invasion of glioma cells by repressing Beclin1 expression. Biochemistry (moscow). 2016; 81: 574-582. [CrossRef]
  167. Chen Y, Liersch R, Detmar M. The miR-290-295 cluster suppresses autophagic cell death of melanoma cells. Sci Rep. 2012; 2: 1-10. [CrossRef]
  168. Liu L, He J, Wei X, Wan G, Lao Y, Xu W, et al. MicroRNA-20a-mediated loss of autophagy contributes to breast tumorigenesis by promoting genomic damage and instability. Oncogene. 2017; 36: 5874-5884. [CrossRef]
  169. Chen Y, Schnitzler KL, Ma Y, Nenkov M, Theis B, Petersen I. The clinical influence of autophagy-associated proteins on human lung cancer. Dis Markers. 2018; 2018: 8314963. [CrossRef]
  170. Hassen D, Bassiouny K, El-Shenawy F, Khalil H. Epigenetics reprogramming of autophagy is involved in childhood acute lymphatic Leukemi. Pediatr Infect Dis. 2017; 2: 282-10045. [CrossRef]
  171. Cruzeiro GA, dos Reis MB, Silveira VS, Lira RC, Neder L, Oliveira RS, et al. HIF1A is overexpressed in medulloblastoma and its inhibition reduces proliferation and increases EPAS1 and ATG16L1 methylation. Curr Cancer Drug Targets. 2018; 18: 287-294. [CrossRef]
  172. Swiderek E, Kalas W, Wysokinska E, Pawlak A, Rak J, Strzadala L. The interplay between epigenetic silencing, oncogenic KRas and HIF-1 regulatory pathways in control of BNIP3 expression in human colorectal cancer cells. Biochem Biophys Res Commun. 2013; 441: 707-712. [CrossRef]
  173. Kim TW, Lee SY, Kim M, Cheon C, Ko SG. Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis. 2018; 9: 1-14. [CrossRef]
  174. Xu Y, An Y, Wang Y, Zhang C, Zhang H, Huang C, et al. miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol Rep. 2013; 29: 2019-2024. [CrossRef]
  175. Hall DP, Cost NG, Hegde S, Kellner E, Mikhaylova O, Stratton Y, et al. TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer Cell. 2014; 26: 738-753. [CrossRef]
  176. Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017; 36: 4929-4942. [CrossRef]
  177. Tiessen I, Abildgaard MH, Lubas M, Gylling HM, Steinhauer C, Pietras EJ, et al. A high-throughput screen identifies the long non-coding RNA DRAIC as a regulator of autophagy. Oncogene. 2019; 38: 5127-5141. [CrossRef]
  178. Wang Z, Zhang S, Li K. LncRNA NEAT1 induces autophagy through epigenetic regulation of autophagy‐related gene expression in neuroglial cells. J Cell Physiol. 2022; 237: 824-832. [CrossRef]
  179. Ullah MF, Usmani S, Shah A, Abuduhier FM. Dietary molecules and experimental evidence of epigenetic influence in cancer chemoprevention: An insight. Semin Cancer Biol. 2022; 83: 319-334. [CrossRef]
  180. Miceli M, Bontempo P, Nebbioso A, Altucci L. Natural compounds in epigenetics: A current view. Food Chem Toxicol. 2014; 73: 71-83. [CrossRef]
  181. Yuqing Yang A, Kim H, Li W, Tony Kong AN. Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr Top Med Chem. 2016; 16: 697-713. [CrossRef]
  182. Lin SR, Fu YS, Tsai MJ, Cheng H, Weng CF. Natural compounds from herbs that can potentially execute as autophagy inducers for cancer therapy. Int J Mol Sci. 2017; 18: 1412. [CrossRef]
  183. Arias C, Salazar LA. Autophagy and polyphenols in osteoarthritis: A focus on epigenetic regulation. Int J Mol Sci. 2021; 23: 421. [CrossRef]
  184. Nur SM, Rath S, Ahmad V, Ahmad A, Ateeq B, Khan MI. Nutritive vitamins as epidrugs. Crit Rev Food Sci Nutr. 2021; 61: 1-13. [CrossRef]
  185. Symonds EL, Konczak I, Fenech M. The Australian fruit Illawarra plum (Podocarpus elatus Endl., Podocarpaceae) inhibits telomerase, increases histone deacetylase activity and decreases proliferation of colon cancer cells. Br J Nutr. 2013; 109: 2117-2125. [CrossRef]
  186. Gao AM, Zhang XY, Hu JN, Ke ZP. Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis. Chem Biol Interact. 2018; 280: 45-50. [CrossRef]
  187. Kim TW. Cinnamaldehyde induces autophagy-mediated cell death through ER stress and epigenetic modification in gastric cancer cells. Acta Pharmacol Sin. 2022; 43: 712-723. [CrossRef]
  188. Liu J, Li M, Wang Y, Luo J. Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition. J Drug Target. 2017; 25: 645-652. [CrossRef]
  189. Guo J, Mei Y, Li K, Huang X, Yang H. Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells. Biochem Biophys Res Commun. 2016; 478: 804-810. [CrossRef]
  190. Tsang WP, Kwok TT. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem. 2010; 21: 140-146. [CrossRef]
  191. Chen Y, Zaman MS, Deng G, Majid S, Saini S, Liu J, et al. MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer. Cancer Prev Res. 2011; 4: 76-86. [CrossRef]
  192. Wang Z, Wang N, Liu P, Chen Q, Situ H, Xie T, et al. MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget. 2014; 5: 7013. [CrossRef]
  193. Huang Y, Du J, Mi Y, Li T, Gong Y, Ouyang H, et al. Long non-coding RNAs contribute to the inhibition of proliferation and EMT by pterostilbene in human breast cancer. Front Oncol. 2018; 8: 629. [CrossRef]
  194. Ferraresi A, Phadngam S, Morani F, Galetto A, Alabiso O, Chiorino G, et al. Resveratrol inhibits IL‐6‐induced ovarian cancer cell migration through epigenetic up‐regulation of autophagy. Mol Carcinog. 2017; 56: 1164-1181. [CrossRef]
  195. Lewinska A, Adamczyk-Grochala J, Deregowska A, Wnuk M. Sulforaphane-induced cell cycle arrest and senescence are accompanied by DNA hypomethylation and changes in microRNA profile in breast cancer cells. Theranostics. 2017; 7: 3461. [CrossRef]
  196. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010; 31: 27-36. [CrossRef]
  197. Chen MY, Liao WS, Lu Z, Bornmann WG, Hennessey V, Washington MN, et al. Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy. Cancer. 2011; 117: 4424-4438. [CrossRef]
  198. Schnekenburger M, Grandjenette C, Ghelfi J, Karius T, Foliguet B, Dicato M, et al. Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy. Bioche Pharmacol. 2011; 81: 364-378. [CrossRef]
  199. Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008; 123: 8-13. [CrossRef]
  200. Ruiz‐Magaña MJ, Rodriguez‐Vargas JM, Morales JC, Saldivia MA, Schulze‐Osthoff K, Ruiz‐Ruiz C. The DNA methyltransferase inhibitors zebularine and decitabine induce mitochondria‐mediated apoptosis and DNA damage in p53 mutant leukemic T cells. Int J Cancer. 2012; 130: 1195-1207. [CrossRef]
  201. Hsieh HY, Shen CH, Lin RI, Feng YM, Huang SY, Wang YH, et al. Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways. Cancer Lett. 2016; 370: 56-65. [CrossRef]
  202. Wang Z, Long QY, Chen L, Fan JD, Wang ZN, Li LY, et al. Inhibition of H3K4 demethylation induces autophagy in cancer cell lines. Biochim Biophys Acta Mol Cell Res. 2017; 1864: 2428-2437. [CrossRef]
  203. Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O’Prey J, Clark W, et al. Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol Cell. 2017; 66: 517-532. [CrossRef]
  204. Yao Y, Hu H, Yang Y, Zhou G, Shang Z, Yang X, et al. Downregulation of enhancer of zeste homolog 2 (EZH2) is essential for the induction of autophagy and apoptosis in colorectal cancer cells. Genes. 2016; 7: 83. [CrossRef]
  205. Yang Y, Zhu F, Wang Q, Ding Y, Ying R, Zeng L. Inhibition of EZH2 and EGFR produces a synergistic effect on cell apoptosis by increasing autophagy in gastric cancer cells. OncoTargets Ther. 2018; 11: 8455. [CrossRef]
  206. Xu H, Zhang L, Qian X, Zhou X, Yan Y, Zhou J, et al. GSK343 induces autophagy and downregulates the AKT/mTOR signaling pathway in pancreatic cancer cells. Exp Ther Med. 2019; 18: 2608-2616. [CrossRef]
  207. Hsieh YY, Lo HL, Yang PM. EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells. Am J Cancer Res. 2016; 6: 1661.
  208. Liu TP, Lo HL, Wei LS, Hsiao HH, Yang PM. S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells. Anticancer Drugs. 2015; 26: 139. [CrossRef]
  209. Mellini P, Marrocco B, Borovika D, Polletta L, Carnevale I, Saladini S, et al. Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells. Philos Trans R Soc B Biol Sci. 2018; 373: 20170150. [CrossRef]
  210. Katona BW, Liu Y, Ma A, Jin J, Hua X. EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells. Cancer Biol Ther. 2014; 15: 1677-1687. [CrossRef]
  211. Park SE, Yi HJ, Suh N, Park YY, Koh JY, Jeong SY, et al. Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB. Oncotarget. 2019; 10: 4348. [CrossRef]
  212. Ren A, Qiu Y, Cui H, Fu G. Inhibition of H3K9 methyltransferase G9a induces autophagy and apoptosis in oral squamous cell carcinoma. Biochem Biophys Res Commun. 2015; 459: 10-17. [CrossRef]
  213. Zhang X, Ma X, Wang Q, Kong Z. EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells. Transl Oncol. 2022; 16: 101316. [CrossRef]
  214. Fan JD, Lei PJ, Zheng JY, Wang X, Li S, Liu H, et al. The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death. PLoS One. 2015; 10: e0116782. [CrossRef]
  215. Ahn MY, Ahn SG, Yoon JH. Apicidin, a histone deaceylase inhibitor, induces both apoptosis and autophagy in human oral squamous carcinoma cells. Oral Oncol. 2011; 47: 1032-1038. [CrossRef]
  216. Ahn MY. HDAC inhibitor apicidin suppresses murine oral squamous cell carcinoma cell growth in vitro and in vivo via inhibiting HDAC8 expression. Oncol Lett. 2018; 16: 6552-6560. [CrossRef]
  217. Ahn MY, Ahn JW, Kim HS, Lee J, Yoon JH. Apicidin inhibits cell growth by downregulating IGF-1R in salivary mucoepidermoid carcinoma cells. Oncol Rep. 2015; 33: 1899-1907. [CrossRef]
  218. Hui KF, Yeung PL, Chiang AK. Induction of MAPK-and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib. Oncotarget. 2016; 7: 4454. [CrossRef]
  219. Zhang J, Ng S, Wang J, Zhou J, Tan SH, Yang N, et al. Histone deacetylase inhibitors induce autophagy through FOXO1-dependent pathways. Autophagy. 2015; 11: 629-642. [CrossRef]
  220. Kong YL, Pan BH, Liang JH, Zhu HY, Wang L, Xia Y, et al. Chidamide, a histone deacetylase inhibitor, inhibits autophagy and exhibits therapeutic implication in chronic lymphocytic leukemia. Aging (Albany NY). 2020; 12: 16083. [CrossRef]
  221. Ratovitski EA. Tumor protein (TP)-p53 members as regulators of autophagy in tumor cells upon marine drug exposure. Mar Drugs. 2016; 14: 154. [CrossRef]
  222. Mehrpouri M, Safaroghli-Azar A, Momeny M, Bashash D. Anti-leukemic effects of histone deacetylase (HDAC) inhibition in acute lymphoblastic leukemia (ALL) cells: Shedding light on mitigating effects of NF-κB and autophagy on panobinostat cytotoxicity. Eur J Pharmacol. 2020; 875: 173050. [CrossRef]
  223. Angeletti F, Fossati G, Pattarozzi A, Würth R, Solari A, Daga A, et al. Inhibition of the autophagy pathway synergistically potentiates the cytotoxic activity of givinostat (ITF2357) on human glioblastoma cancer stem cells. Front Mol Neurosci. 2016: 107. [CrossRef]
  224. Bhalla S, Evens AM, Prachand S, Schumacker PT, Gordon LI. Paradoxical regulation of hypoxia inducible factor-1α (HIF-1α) by histone deacetylase inhibitor in diffuse large B-cell lymphoma. PLoS One. 2013; 8: e81333. [CrossRef]
  225. Kommalapati VK, Kumar D, Tangutur AD. Inhibition of JNJ-26481585-mediated autophagy induces apoptosis via ROS activation and mitochondrial membrane potential disruption in neuroblastoma cells. Mol Cell Biol. 2020; 468: 21-34. [CrossRef]
  226. Roberts JL, Poklepovic A, Booth L, Dent P. The multi-kinase inhibitor lenvatinib interacts with the HDAC inhibitor entinostat to kill liver cancer cells. Cell Signal. 2020; 70: 109573. [CrossRef]
  227. El-Khoury V, Pierson S, Szwarcbart E, Brons NH, Roland O, Wilde CD, et al. Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia. Leukemia. 2014; 28: 1636-1646. [CrossRef]
  228. Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci. 2004; 101: 18030-18035. [CrossRef]
  229. Marampon F, Leoni F, Mancini A, Pietrantoni I, Codenotti S, Letizia F, et al. Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma. J Cancer Res Clin Oncol. 2019; 145: 393-409. [CrossRef]
  230. Park JH, Ahn MY, Kim TH, Yoon S, Kang KW, Lee J, et al. A new synthetic HDAC inhibitor, MHY218, induces apoptosis or autophagy-related cell death in tamoxifen-resistant MCF-7 breast cancer cells. Invest New Drugs. 2012; 30: 1887-1898. [CrossRef]
  231. Klein JM, Henke A, Sauer M, Bessler M, Reiners KS, Engert A, et al. The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines. PLoS One. 2013; 8: e79502. [CrossRef]
  232. Lachenmayer A, Toffanin S, Cabellos L, Alsinet C, Hoshida Y, Villanueva A, et al. Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib. J Hepatol. 2012; 56: 1343-1350. [CrossRef]
  233. Rao R, Balusu R, Fiskus W, Mudunuru U, Venkannagari S, Chauhan L, et al. Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cellspanobinostat and chloroquine against breast cancer. Mol Cancer Ther. 2012; 11: 973-983. [CrossRef]
  234. Liu YL, Yang PM, Shun CT, Wu MS, Weng JR, Chen CC. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy. 2010; 6: 1057-1065. [CrossRef]
  235. Yamamoto S, Tanaka K, Sakimura R, Okada T, Nakamura T, Li Y, et al. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res. 2008; 28: 1585-1591.
  236. Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci. 2012; 109: 6561-6565. [CrossRef]
  237. Goncalves RM, Agnes JP, Delgobo M, de Souza PO, Thomé MP, Heimfarth L, et al. Late autophagy inhibitor chloroquine improves efficacy of the histone deacetylase inhibitor SAHA and temozolomide in gliomas. Biochem Pharmacol. 2019; 163: 440-450. [CrossRef]
  238. Lee YJ, Won AJ, Lee J, Jung JH, Yoon S, Lee BM, et al. Molecular mechanism of SAHA on regulation of autophagic cell death in tamoxifen-resistant MCF-7 breast cancer cells. Int J Medical Sci. 2012; 9: 881. [CrossRef]
  239. Lee JY, Kuo CW, Tsai SL, Cheng SM, Chen SH, Chan HH, et al. Inhibition of HDAC3-and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells. Front Pharmacol. 2016; 7: 81. [CrossRef]
  240. New M, Olzscha H, Liu G, Khan O, Stimson L, McGouran J, et al. A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors. Cell Death Differ. 2013; 20: 1306-1316. [CrossRef]
  241. Newbold A, Vervoort SJ, Martin BP, Bots M, Johnstone RW. Induction of autophagy does not alter the anti-tumor effects of HDAC inhibitors. Cell Death Dis. 2012; 3: e387. [CrossRef]
  242. Chiu HW, Yeh YL, Wang YC, Huang WJ, Chen YA, Chiou YS, et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, enhances radiosensitivity and suppresses lung metastasis in breast cancer in vitro and in vivo. PLoS One. 2013; 8: e76340. [CrossRef]
  243. Yang F, Wang F, Liu Y, Wang S, Li X, Huang Y, et al. Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells. Life Sci. 2018; 213: 149-157. [CrossRef]
  244. Wang W, Lv M, Zhao X, Zhang J. Developing a novel indolocarbazole as histone deacetylases inhibitor against leukemia cell lines. J Anal Methods Chem. 2015; 2015: 675053. [CrossRef]
  245. Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, et al. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int J Cancer. 2009; 124: 55-67. [CrossRef]
  246. Dong LH, Cheng S, Zheng Z, Wang L, Shen Y, Shen ZX, et al. Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma. J Hematol Oncol. 2013; 6: 1-11. [CrossRef]
  247. Stankov MV, El Khatib M, Kumar Thakur B, Heitmann K, Panayotova-Dimitrova D, Schoening J, et al. Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia. 2014; 28: 577-588. [CrossRef]
  248. Ji MM, Wang L, Zhan Q, Xue W, Zhao Y, Zhao X, et al. Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation. Autophagy. 2015; 11: 2160-2171. [CrossRef]
  249. Saha SK, Yin Y, Kim K, Yang GM, Abdal Dayem A, Choi HY, et al. Valproic acid induces endocytosis-mediated doxorubicin internalization and shows synergistic cytotoxic effects in hepatocellular carcinoma cells. Int J Mol Sci. 2017; 18: 1048. [CrossRef]
  250. Füllgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013; 500: 468-471. [CrossRef]
  251. Takemoto Y, Ito A, Niwa H, Okamura M, Fujiwara T, Hirano T, et al. Identification of cyproheptadine as an inhibitor of SET domain containing lysine methyltransferase 7/9 (Set7/9) that regulates estrogen-dependent transcription. J Med Chem. 2016; 59: 3650-3660. [CrossRef]
  252. Feng S, Jin Y, Cui M, Zheng J. Lysine-specific demethylase 1 (LSD1) inhibitor S2101 induces autophagy via the AKT/mTOR pathway in SKOV3 ovarian cancer cells. Med Sci Monit. 2016; 22: 4742. [CrossRef]
  253. Liu S, Lu W, Li S, Li S, Liu J, Xing Y, et al. Identification of JL1037 as a novel, specific, reversible lysine-specific demethylase 1 inhibitor that induce apoptosis and autophagy of AML cells. Oncotarget. 2017; 8: 31901. [CrossRef]
  254. Etani T, Suzuki T, Naiki T, Naiki-Ito A, Ando R, Iida K, et al. NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect. Oncotarget. 2015; 6: 2865. [CrossRef]
  255. Ambrosio S, Saccà CD, Amente S, Paladino S, Lania L, Majello B. Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway. Oncogene. 2017; 36: 6701-6711. [CrossRef]
  256. Chao A, Lin CY, Chao AN, Tsai CL, Chen MY, Lee LY, et al. Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies. Oncotarget. 2017; 8: 74434. [CrossRef]
  257. Wei Y, Han T, Wang R, Wei J, Peng K, Lin Q, et al. LSD1 negatively regulates autophagy through the mTOR signaling pathway in ovarian cancer cells. Oncol Rep. 2018; 40: 1196. doi: 10.3892/or.2018.6495. [CrossRef]
  258. Wang J, Kim TH, Ahn MY, Lee J, Jung JH, Choi WS, et al. Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. Int J Oncol. 2012; 41: 1101-1109. [CrossRef]
  259. Tae IH, Park EY, Dey P, Son JY, Lee SY, Jung JH, et al. Novel SIRT1 inhibitor 15-deoxy-Δ12, 14-prostaglandin J2 and its derivatives exhibit anticancer activity through apoptotic or autophagic cell death pathways in SKOV3 cells. Int J Oncol. 2018; 53: 2518-2530. [CrossRef]
  260. De U, Son JY, Sachan R, Park YJ, Kang D, Yoon K, et al. A new synthetic histone deacetylase inhibitor, MHY2256, induces apoptosis and autophagy cell death in endometrial cancer cells via p53 acetylation. Int J Mol Sci. 2018; 19: 2743. [CrossRef]
  261. Park EY, Woo Y, Kim SJ, Lee EK, De U, Kim KS, et al. Anticancer effects of a new SIRT inhibitor, MHY2256, against human breast cancer MCF-7 cells via regulation of MDM2-p53 binding. Int J Biol Sci. 2016; 12: 1555. [CrossRef]
  262. Gez S, Crossett B, Christopherson RI. Differentially expressed cytosolic proteins in human leukemia and lymphoma cell lines correlate with lineages and functions. Biochim Biophys Acta Proteins Proteom. 2007; 1774: 1173-1183. [CrossRef]
  263. Iachettini S, Trisciuoglio D, Rotili D, Lucidi A, Salvati E, Zizza P, et al. Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells. Cell Death Dis. 2018; 9: 1-12. [CrossRef]
  264. Jang JE, Eom JI, Jeung HK, Cheong JW, Lee JY, Kim JS, et al. AMPK–ULK1-mediated autophagy confers resistance to BET inhibitor JQ1 in acute myeloid leukemia stem cells. Clin Cancer Res. 2017; 23: 2781-2794. [CrossRef]
  265. Ouyang L, Zhang L, Liu J, Fu L, Yao D, Zhao Y, et al. Discovery of a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer. J Med Chem. 2017; 60: 9990-10012. [CrossRef]
Journal Metrics
2023
CiteScore SJR SNIP
0.40.1600.093
Newsletter
Download PDF Download Full-Text XML Download Citation
0 0
Newsletter  

TOP