Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies.
Bottom Line: Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo.Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression.Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.
Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.Show MeSH
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Mentions: We used the R1-AD1/R1-D567 model to study genome-wide AR and ARv567es binding via ChIP-seq using an antibody targeted to the AR NH2-terminal domain (NTD). Peak calling with data from a single ChIP-seq experiment resulted in the identification of 12 030 AR binding sites in R1-AD1 cells and 3554 ARv567es binding sites in R1-D567 cells (Figure 2A and B, Supplemental Table S4). Motif analysis revealed enrichment of canonical androgen response elements (AREs) in both R1-AD1 and R1-D567 cells (Figure 2C, Supplemental Table S5). Further motif analysis revealed that occurrences of stringent and relaxed specificity AREs (33) were similar in both datasets (Supplemental Table S6). These data indicate that regulation of AR and ARv567es DNA binding may proceed through similar mechanisms.
Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.