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Cell, Molecular, and Tumor Biology: Gene Regulation and Transcriptional Control

Downregulation of novel AR target genes.

Norris Cancer Center/University of Southern California, Los Angeles, CA; Institute for Genetic Medicine/University of Southern California, Los Angeles, CA

Abstract

A129

Interest in androgen receptor (AR) target genes and in the regulation of AR signaling continues as a result of the receptor's involvement in prostate tumorigenesis. Numerous studies have been devoted to identifying and understanding AR-mediated mechanisms of prostate cancer initiation and progression. Until recently, efforts have been disproportionately spent on studying the androgen-mediated mechanisms of upregulated genes, such as prostate specific antigen (PSA), as compared to downregulated genes, which may be involved in growth inhibitory and pro-apoptotic pathways. In the present study we employed AR ChIP Display (CD), an affordable and unbiased approach to discover genome-wide AR binding sites, in the hormone-refractory cell line, C4-2B. We have identified a subset of 3 novel DHT-mediated downregulated genes in the vicinity of AR binding regions. They are the cholinergic receptor, muscarinic 1 (CHRM1), the Williams-Beuren syndrome chromosome region 28 (WBSCR28) and a transcript of unknown function (KIAA1217). Site-specific primers were used to validate the identified binding sites, while time-course and real-time RT-PCR experiments examined the DHT responsiveness of genes in the vicinity of validated AR binding regions. DHT dose response and AR-specific siRNA experiments determined the AR dependence of gene repression. Pre-mRNA analysis indicated direct AR-mediated transcriptional repression, which could be reversed upon treatment with the anti-androgen, bicalutamide. The identification of negative AR-mediated transcriptional mechanisms will aid in the understanding of AR-mediated progression of prostate cancer.