Abstract IA19: Cooperation between androgen receptor and Polycomb in prostate cancer

Abstract

Abstract Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development, function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Although androgen stimulation has been shown to also suppress genes, little attention has been paid to the mechanisms and functions of AR-mediated gene repression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is dictated, at least in part, by the Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells (ESC), AR-repressed genes harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of developmental regulators, the silencing of which maintains the undifferentiated ESC state. Similarly, these genes are down-regulated in poorlydifferentiated, castration-resistant prostate tumors rendering a stem cell-like cellular state. To characterize the function of AR-repressed genes, we nominated NOV as a top AR-repressed gene. We show that NOV is robustly suppressed by androgen through the AR. Using NOV as a model gene we present evidence that AR directly inhibits gene expression through physically binding to the enhancer, establishing promoter-enhancer DNA looping, and inducing repressive chromatin remodeling. We further demonstrate that NOV is down-regulated in aggressive prostate cancer. Concordantly, NOV expression inhibits prostate cancer cell growth, migration, and invasion in vitro and xenograft tumor growth in mice. Collectively, our data reveal an unexpected role of AR in inhibiting non-prostatic differentiation and, upon aberrant signaling, promoting cancerous de-differentiation. Our findings support AR-mediated inhibition of tumor suppressors as a novel mechanism to prostate cancer progression. Citation Format: Jonathan C. Zhao, Christine Runkle, Jianjun Yu, Longtao Wu, Hongjian Jin, Timothy Kuzel, Chung Lee, Jindan Yu. Cooperation between androgen receptor and Polycomb in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA19.