Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in American men. While organ-confined PCa can be effectively eradicated through surgical and radiation therapies, metastatic disease is essentially incurable. Androgen signaling mediated through the androgen receptor (AR) is one of the most important pathways in PCa initiation and progression. Hormone-deprivation has thus been the standard, first-line treatment for metastatic PCa. Interestingly, in the late-stage castration-resistant PCa (CRPC), AR has become activated, rather than insensitive, in a low androgen environment, thus being responsible for castration resistance. Therefore, understanding and targeting AR pathway remains a central challenge in PCa research. While AR signaling has been studied for decades, it is incompletely understood with past focus largely on genes induced by the AR. Interestingly, recent studies, including ours, have started to show AR also as a globally acting transcriptional repressor. Further, our data suggest that this repression is mediated by the polycomb group protein EZH2 and repressive chromatin remodeling around the target genes. However, a model gene that is representative of this innovative role of AR is needed to further delineate the mechanistic details of AR-mediated repression and, most importantly, to appreciate the functional relevance and therapeutic importance of this repression. Through meta-analysis of androgen-regulated expression microarray data, we nominated NOV (CCN3) as a top candidate. Our preliminary data suggest that NOV is a novel gene of great importance in PCa. It is inhibited by AR and EZH2 and is markedly down-regulated in advanced PCa. Functional analysis suggests that NOV inhibits PCa progression and its loss-of-function drives castration resistance. We thus hypothesize that NOV is directly suppressed by AR through repressive chromatin remodeling and plays essential roles in PCa progression. To address this hypothesis, three specific aims are proposed. In Aim 1, we will determine androgen regulation and NOV expression in prostate cancer, including patient samples. In Aim 2, we will examine how AR inhibits NOV expression in prostate cancer cells. We will determine if AR directly binds to the NOV gene promoter and/or enhancer, map chromatin changes around the gene, and examine whether/how EZH2 is response for these changes and thus gene repression. Aim 3 will investigate the functional role of NOV in regulating PCa proliferation, migration, invasion/metastasis, and castration resistance using cell line models and nude mice.