Prostate cancer (PCa) remains a leading cause of death in men. Androgen Receptor (AR) plays a central role in normal prostate development as well as regulating cell proliferation, differentiation and apoptosis in PCa. Resultantly, AR remains a valuable therapeutic target due to this organ specificity. Although it is known that CBP/p300 (CREB binding protein) mediated lysine acetylation of AR (ARKac) plays a vital role in AR activation and control of downstream target genes in prostate cells, the molecular events that follow ARKac remains unclear. Our study elucidated the mechanistic details of molecular events that follow CBP mediated acetylation of p53 on lysine 382 (p53Kac382) upon genotoxic stress. We showed that CBP is recruited to p53K382ac moiety by its bromodomain (CBP BRD): a specific molecular interaction that is essential for p53-induced transcriptional activation of the cyclin dependent kinase inhibitor, p21, involved in G1 cell cycle arrest. Preliminary data show that a small molecule inhibitor (SMI) of CBP BRD inhibits AR expression and transcriptional activity by downregulating prostate specific antigen (PSA) in LNCaP and PC3 cells. Here, we hypothesize that CBP BRD play a key role in ARKac-mediated regulation of target genes and cell fate decisions;therefore, highly selective SMIs for CBP BRD could alter the fate of the cancer cells to apoptosis. Therefore, the long-term goal of this research plan is to block the AR function in PCa. While multiple acetylation sites in AR have been reported, the specific effects of individual or combined acetylation of these lysine residues on AR activity remains to be clarified. Further, despite AR being a sequence-specific DNA binding transcription factor, the role of PTMs on chromatin as well as AR in regulating downstream genes is unknown. A multifaceted approach is proposed to address mechanistic underpinnings of AR transcriptional activation as a consequence of acetylation.
Two specific aims are proposed to achieve this goal: (1) validate CBP BRD as a new therapeutic target for PCa;(2) dissect cellular response concomitant with epigenetic changes on global chromatin and AR target gene PSA. The emerging results from the proposed studies are expected to enhance our understanding of the molecular basis of AR function. Given the central role of AR in PCa, these studies will have important implications for the prognosis and treatment of human tumors.
Lysine acetylation (Kac) of Androgen Receptor (ARKac) by CREB-binding protein (CBP) leads to AR activation in PCa cells. We demonstrated that Kac recruit bromodomain (BRD) containing proteins that control cellular outcomes. Preliminary data shows that small molecule inhibitor of CBP BRD inhibit AR activity. Therefore, the objective of this study is to validate CBP BRD as new therapeutic target.
