Exploring the Role of BET Bromodomain Proteins in AR Transcriptional Regulation: A Perpetuating Cycle of JQ1 Resistance in CRPC Therapy
Abstract
Prostate cancer (PC) depends critically on androgen receptor (AR) for its growth and progression to highly metastatic stage, called as castration-resistant prostate cancer (CRPC). Not surprisingly, a large majority of current prostate cancer therapies revolve around inhibition of AR activity. Unfortunately, despite the prolonged AR antagonist treatment, expression of AR is not abated, suggesting that suppression AR mRNA and protein is the Achilles heel to achieve therapeutic benefit for CRPC patients. Recently, it was demonstrated that PC cell lines exhibit sensitivity to a BET bromodomain inhibitor, JQ1, which disrupts BET bromodomain of BRD4 interaction with AR. Interestingly, it revealed that JQ1 increased AR transcription, suggesting an existence of an AR transcriptional repressor that is directly regulated by the BRD4-AR complex, which maintains AR homeostasis. This would explain why the cells treated with JQ1 would prevent transcription of the AR repressor, consequently inducing AR transcription. In this proposal, we will test the hypothesis that BCOR is the AR repressor and treatment of CRPCs with JQ1 leads to robust increase in AR levels, making them resistant to JQ1 and other BET bromodomain inhibitors. Overall, this proposal will obtain precise mechanistic details by which JQ1 promotes upregulation of AR in CRPCs and elucidate the raison d ?tre why JQ1 could be counterproductive for CRPC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510660
Entities
People
- Kiran Mahajan
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army