Abstract 121: Novel epigenetic mechanisms of resveratrol regulation of PTEN/Akt pathway in prostate cancer

Abstract

Abstract Resveratrol (Res) (3,5,4′-trihydroxy-trans-stilbene), a natural compound found in grapes and berries, is one of the most promising diet-derived chemopreventive agent with potential chemotherapeutic capabilities. Chemopreventive and anticancer effects of Res may be exerted in part by modulating various components of the epigenetic machinery. We recently demonstrated that Res represses nucleosome remodeling and deacetylation (NuRD) co-repressor complex by inhibiting metastasis associated protein 1/ histone deacetylase 1 (MTA1/HDAC1) subunit, which plays an essential role in governing deacetylation of histone and non-histone proteins. Since Res-induced upregulation of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is concomitant with MTA1-downregulation, we hypothesized that in the absence of Res MTA1 works in cooperation with PI3K/Akt survival pathways. We further hypothesized that Res-induced restoration of PTEN expression and function may occur by dual mechanism through MTA1/HDAC inhibition and regulation of miRNA network. Our data indicate that shRNA-mediated MTA1 knockdown in Du145 cells (wt PTEN) enhances acetylation of PTEN, and that HDAC inhibitor trichostatin (TSA) further potentiates PTEN acetylation. We also showed that Res treatment simultaneously decreases MTA1 and pAkt levels in LNCaP cells, the effect which is enhanced in combination with PI3K inhibitors, LY294002 and BEZ235. To further understand Res-induced MTA1-mediated epigenetic alterations, we analyzed MTA1-associated and Res-induced microRNA (miRNA, miR) changes in LNCaP cells expressing and silenced for MTA1 (shMTA1). Interestingly, Res downregulated miRs (oncomiRs) included members of miR17-92 cluster (miRs-17, 20a, 20b) and miRs 106a and 106b which target PTEN. These findings were further confirmed by real time PCR analysis which showed that Res specifically down-regulated these miRNAs in PCa cells (LNCaP and Du145) but not in normal prostate cell line RWPE-1. Direct interaction of miR-17, miR-20a and miR-106b with PTEN 3′UTR were analyzed in the presence and absence of Res using pmiRGLO luciferase reporter. In summary, we propose novel epigenetic mechanisms of Res regulation of PTEN/ Akt signaling through inhibition of MTA1/NuRD co-repressor complex and MTA1-associated miRNAs. 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 121. doi:1538-7445.AM2012-121