Exploring the Role of BET Bromodomain Proteins in AR Transcriptional Regulation: A Perpetuating Cycle of JQ1 Resistance in CRPC Therapy
Abstract
During the inevitable progression to castration resistant stage, prostate cancer cells acquire resistance to anti-androgens.Paradoxically, despite the prolonged AR antagonist treatment, expression of AR is not abated in CRPCs, signifying AR as the Achilles heel to achieve realistic therapeutic benefit in CRPC patients. Recently, it has been reported that prostate cancer cells positive for AR-signaling and CRPC xenograft tumors display exquisite sensitivity to JQ1, a BET bromodomain inhibitor. Mechanistically, JQ1 binds the N-terminal BET bromodomain of BRD4 to disrupt its interaction with AR and prevent expression of DHT dependent AR target genes. Ironically, while JQ1 ablated AR target gene transcription, it significantly increased AR transcription and this increase was concomitant with increasing concentrations of JQ1 treatment. This incongruous observation suggests that in androgen-responsive PC cells, AR-BRD4 interaction may regulate AR transcription by a negative feedback loop. One potential mechanism is the presence of an AR transcriptional repressor that is directly regulated by the BRD4-AR complex, which maintains AR homeostasis. The hypothesis is that in cells treated with JQ1, inhibition of BRD4-AR signaling would prevent transcription of the AR repressor, consequently inducing AR transcription. Thus, greater the JQ1 mediated inhibition, greater is the up regulation of AR. Additionally, since only a fraction of the AR binding sites are co-enriched for BRD4 binding in androgen stimulated PC cells, JQ1 mediated inhibition will at the most have a modest effect on long-term CRPC treatments. It is this BRD4-independent AR target gene expression that will continue to promote CRPCs progression and metastasis. This proposal will explore novel molecular mechanisms by which prostate cancer cells develop resistance to BET bromodomain inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2016
- Accession Number
- AD1030613
Entities
People
- Kiran Mahajan