Abstract 2582: 2-ME2-induced biological effects in prostate cancer: Role for miR127-3p/SET8

Prostate cancer is the second most common cause of death related to cancer in Western societies. 2-Methoxyestradiol (2-ME2), an endogenous metabolite of 17-α estradiol inhibits tumor cell proliferation in various cancer cells, including the prostate. Previous studies from our laboratory showed that 2-ME2 (i) inhibits proliferation of both androgen responsive and independent cells through induction of apoptosis involving G2/M check point block; (ii) prevents the development of prostate tumors in transgenic adenocarcinoma of mouse prostate (TRAMP) model. Although various molecular targets have been proposed, the mechanism of action behind its antiproliferative activity is still uncertain. Here we investigated the possible role for 2-ME2 induced antiproliferative activity by examining the altered regulation of microRNA (miRNAs). MicroRNA expression profiling identified miR127-3p as most significantly up regulated in response to 2-ME2 treatment in androgen independent (PC-3) cells. We have also identified histone methylase SET8 as a potential target of miR 127-3p. We have validated these data using Q-PCR. Further 2-ME2 treatment reduced binding of multiple transcription factors including Sp1, Sp3 and NFκB to the FLIP promoter as evidenced by transient expression assays, ChIP and gel-shift assays. Our findings indicate that 2-ME2 suppresses proliferation and induces apoptosis in prostate cancer cells possibly through miR127-3p/SET8 mediated regulation of FLIP. Supported by NIH CA 135451 (APK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2582. doi:1538-7445.AM2012-2582