Abstract 3535: Epigenetic regulation of miR-31 and miR-205 of apoptosis in prostate cancer

Abstract

Abstract Prostate cancer is the second leading cause of cancer-related mortality among men in the United States. However, our understanding of the cause of prostate cancer remains elusive. Recent studies have implicated that epigenetics, heritable changes in gene expression caused by mechanisms other than classical genetic alterations, is an important mechanism in tumorigenesis. MicroRNAs function as epigenetic regulators to alter gene expression, and very limited information is available regarding the roles of microRNAs in prostate cancer. Evasion of apoptosis is the hallmark of cancer, and it plays an important role in the growth and development of prostate cancer. We have recently demonstrated that miR-31 and miR-205 are downregulated in advanced prostate cancer. In addition, anti-apoptotic protein E2F6 was identified as the target of miR-31 and contributed resistance to chemotherapy-induced apoptosis. While we found that miR-205 is silenced by gene promoter methylation, the mechanism of the downregulation of miR-31 in prostate cancer remains poorly defined. In this study, we report that EZH2 (Enhancer of zeste 2), a histone methyltransferase and component of the polycomb repressive complex 2 (PRC2), is responsible for miR-31 silencing in prostate cancer. EZH2 plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Our results have shown that siRNA knockdown of EZH2 and DZNep (3-deazaneplanocin) treatment (an EZH2 inhibitor) in prostate cancer cells increased miR-31 expression. Furthermore, EZH2 is responsible for histone methylation at the promoter of miR-31 gene. In addition, siRNA knockdown of EZH2 and the treatment with DZNep sensitized prostate cancer cells to apoptosis. In contrast, EZH2 overexpression confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Thus, polycomb protein EZH2 suppresses the expression of miR-31 and consequently contributes to apoptosis resistance in prostate cancer. The results will improve our understanding of the mechanism of drug resistance in prostate cancer cells. Novel strategies targeting EZH2 and miR-31 can be developed to increase drug-induced apoptosis and improve cancer response to chemotherapy. Citation Format: Qunshu Zhang. Epigenetic regulation of miR-31 and miR-205 of apoptosis in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2014-3535