While AR has been extensively characterized as a transcriptional activator, it was recently reported to function as a transcriptional repressor to suppress a subset of genes. Significantly, through AR ChIP-seq and transcriptome profiling in prostate cancer cells we have found that the directly AR-repressed genes are highly enriched for DNA replication function and majority of those genes were consistently increased in CRPC clinical samples. We then discovered that this direct transcriptional repression activity of AR was mediated by androgen-stimulated recruitment of hypophosphorylated Rb. Androgens is also known to stimulate growth by further AR transcriptional activation of genes driving lipid and sterol synthesis, and other metabolic functions, with subsequent cyclin dependent kinase activation and Rb hyperphosphorylation. Overexpression of AR in prostate cancer cells could overcome this growth stimulatory effect. These findings demonstrate that AR has an Rb-dependent anti-proliferative function, which may be compromised in CRPC cells with Rb-deficiency and could be enhanced by blocking Rb phosphorylation. The objective of this proposal is to determine the function roles of AR recruitment of Rb in regulating transcription of DNA replication genes and cell cycle progression of PCa tumor cells (specific aim 1), to determine the molecular basis for AR interaction with hypophosphorylated Rb and characterize the distinct Rb complex recruited by AR to the suppression sits (specific aim 2), and to conduct a genome wide analysis to identify Rb dependent AR suppression sites and determine the mechanism of actions and function roles of these sites in prostate cancer cells (specific aim 3).
While androgen receptor (AR) has been extensively characterized as a transcription activator, it can function as a transcription repressor to suppress genes mediating DNA replication and cell cycle, providing a rational for treating castration resistant prostate cancer with high doses androgen. Recently, we have discovered that this tumor suppressor function of AR depends on the recruitment of hypophosphorylated Retinoblastoma Protein (Rb) to enhance Rb mediated repression of E2Fs. In this proposal, we are trying to elucidate the global mechanism of AR recruitment of Rb, and assess the impact of Rb expression level and its phosphorylation on the growth suppressive function of AR in castration-resistant prostate cancer models.
