Rethinking Demethylating Agents in Epigenetic Cancer Therapy
Received Date: Jun 08, 2016 / Accepted Date: Jun 23, 2016 / Published Date: Jun 27, 2016
DNA methylation inhibitors 5-Azacytidine and 5-Aza-2’-deoxycytidine have been increasingly used in the clinic to treat myeloid disorders and cancer since their FDA approval over a decade ago. Increasing the efficiency and efficacy of these drugs require better understanding on their mechanism of action. Recent studies show that DNA methylation inhibitors have widespread anti-tumor functions and act by modulating oncogenes and tumor suppressor genes expression as well as stimulating the immune system. These findings demonstrate the significant progress that has been made in the field of epigenetic therapy to improve patients’ outcome.
Keywords: DNA methylation; Epigenetic theraphy; Oncogenes
Letter To The Editor
Our understanding of how to use DNA methyltransferase (DNMT) inhibitors to target DNA methylation in cancer therapy have come a long way since the nucleotide analogs 5-Azacytidine (5-Aza-CR, Vidaza) and 5-Aza-2’-deoxycytidine (5-Aza-2-CdR, Decitabine) were approved by the FDA over a decade ago for the treatment of myeloid dysplastic syndrome. First developed as chemotherapeutic agents, these compounds (hereon referred collectively as AZA) were found to reduce DNA methylation level in tumor cells, thus acting as demethylating agents [1,2]. DNA methylation is a covalent addition of a methyl group at the fifth carbon of cytosines that are present in the context of CpG dinucleotides. DNA methylation is a component of epigenetic machineries, which in normal cells, is critical for silencing of retrotransposons, and during genomic silencing and X-inactivation. Although the levels may vary, global changes in DNA methylation have been shown to be a key feature of cancer cells. Furthermore, DNA methylation is dynamic and pharmacologically reversible and thus, an attractive target for cancer therapy.
Decades of study have shown that while cancer cells exhibit global decrease in DNA methylation, there are punctate regions throughout the genome that have markedly increased DNA methylation level. This hypermethylation pattern is strongly associated with the silencing of genes, including tumor suppressor genes, leading to gene expression profile that favor uncontrollable cell growth. These observations help shaped the traditional view on DNMT inhibitors therapy that at lowdose, AZA is non-cytotoxic and consequently, can be used to induce DNA demethylation and reactivate tumor suppressor genes to reverse malignant phenotype [3,4]. Yet, while AZA treatment directly results in DNA demethylation, the level of demethylation does not always correlate with the level of tumor suppressor genes reactivation and/or predict clinical outcome. Questions thus remained on the mechanism governing AZA’s anti-tumor activities.
The advancement in epigenomic studies in recent years, has revealed that the function of DNA methylation is nuanced and very much dependent on the genomic context in which it occurs . This understanding influences how we approach the use of AZA in epigenetic therapy. While DNA methylation found in promoters is associated with gene silencing, for instance, DNA methylation found in gene bodies is thought to be associated with active transcription. Consequently, in the context of gene bodies, AZA-mediated demethylation has the effect of decreasing overexpressed oncogenes such as c-MYC, as well as other metabolic regulatory genes that are often induced during the initiation of tumorigenesis . This result suggests that downregulation of oncogenes may mediate AZA’s antiproliferative effects, and likely complement previously described upregulation of tumor suppressor genes. Kinetically, the effects of AZA also vary, with gene bodies becoming selectively remethylated faster than the promoters following drug withdrawal in DNMT3Bdependent pathway. This mechanism suggests pharmacological specificity in the otherwise non-specific demethylating agents .
Recent investigations on the mechanism of actions of AZA in solid tumors further reveal that the anti-tumor activities of AZA are not limited to modulating canonical oncogenes and tumor suppressor genes. Independently, preclinical studies by Chiappinelli et al.  and Roulois et al.  show that AZA induces demethylation of previously silenced endogenous retrovirus elements (ERVs) in colorectal and ovarian cancer which triggers the robust activation of IRF7 interferon response pathways. ERVs make up about 8% of the human genome, an evolutionary consequence of viral infection and viral sequence insertion. In normal cells, the expression of these ERVs is kept in check by DNA hypermethylation. Upon removal of DNA methylation, bidirectional transcription of ERVs is activated, resulting in the production of dsRNA that stimulates MDA5 and RIG-1 proteins and subsequent IRF7 activation. In turn, the activation of anti-viral defense mechanism sensitizes tumor cells to anti-CTLA4 immune checkpoint therapy . These results build upon previous studies that show that AZA treatment activates the expression of tumor antigens and the immunosuppressive PDL1, demonstrating an immune layer by which AZA works to promote anti-tumor activities . Altogether, these findings represent an exciting potential for the future use of AZA both as a stand-alone drug and as a bridge between epigenetic and immune cancer therapy.
- Yang X, Lay F, Han H, Jones PA (2010) Targeting DNA methylation for epigenetic therapy. Trends in pharmacological sciences 31: 536-546.
- Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation.Cell 20: 85-93.
- Yang X (2012) Gene reactivation by 5-aza-2'-deoxycytidine-induced demethylation requires SRCAP-mediated H2A.Z insertion to establish nucleosome depleted regions. PLoS genetics 8: e1002604.
- Tsai HC, Li H, Van Neste L, Cai Y, Robert C, et al. (2012)Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.Cancer cell 21: 430-446.
- Jones PA (2012) Functions of DNA methylation: islands,start sites, gene bodies and beyond. Nature reviews Genetics 13: 484-492.
- Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, et al. (2014) Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer cell 26: 577-590.
- Kasinathan S, Henikoff S (2014) 5-Aza-CdR delivers a gene body blow. Cancer cell 26: 449-451.
- Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, et al. (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNAincluding endogenous retroviruses.Cell 162: 974-986.
- Roulois D, Yau LH, Singhania R, Wang Y, Danesh A, et al. (2015) DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162: 961-973.
- Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, et al. (2014) Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5: 587-598.
Citation: Lay FD, Liang G (2016) Rethinking Demethylating Agents in Epigenetic Cancer Therapy. J Mol Pharm Org Process Res 4: 133. Doi: 10.4172/2329-9053.1000133
Copyright: ©2016 Lay FD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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