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DNMT Inhibitors Increase Methylation in the Cancer Genome.

ABSTRACT: DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (|r|? 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.

SUBMITTER: Giri AK

PROVIDER: S-EPMC6491738 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with cases increasing dramatically in the USA. Developing more effective targeted therapies for HCC is an urgent need. The FDA-approved DNA methyltransferase inhibitors (DNMTis) 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2’-deoxycytidine (5-aza-CdR, Decitabine) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, the clinical efficacies of DNMTis are still limited, in part due to an “epigenetic switch” mechanism, in which a large group of genes demethylated by DNMTi treatment remain silenced by Polycomb Repressive Complex 2 (PRC2) occupancy. Overexpression of PRC2 subunits, especially EZH2, is correlated with poor patient survivor in HCC. In this study, we tested the combination of 5-Aza-CdR and the EZH2 inhibitor (EZH2i) GSK-126 in human HCC cell lines (SNU398, HepG2, and SNU475) on DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all cell lines showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently silenced genes. The increased number of up-regulated genes, including tumor suppressors, were correlated with prolonged anti-proliferation effects and nucleosome accessibility but negatively correlated with gene promoter DNA methylation. Detailed epigenome analyses reveal a mechanistic rationale in which the combination treatment of 5-aza-CdR with an EZH2 inhibitor (EZH2i) activates demethylated promoters that are repressed by PRC2 occupancy. Furthermore, about 13.6% to 31% of genes down-regulated by DNA methylation in primary HCC tumors can be reactivated through this combination treatment scheme in vitro. Finally, combination treatment also exacerbates viral mimicry activation as well as leukocyte, lymphocyte and T cell mediated immunity, while most those genes or pathways were downregulated in over 50% of primary HCC tumors in TCGA dataset. Conclusion: we have linked the anti-tumor effects of DNMTi and EZH2i combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for combination treatment efficacy in HCC patients.

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DNMT Inhibitors Increase Methylation in the Cancer Genome.

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