Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies.
Bottom Line: Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation.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.
Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.Show MeSH
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Mentions: In a previous study, the inhibitory effects of JQ1 on AR chromatin binding were attributed to a direct interaction between AR and BRD4 (28). We hypothesized our novel finding of down-regulated AR and AR-V expression following JQ1 treatment represented an important component of the JQ1 anti-AR mechanism of action, reminiscent of down-regulated MYC expression in multiple myeloma cells (50,51). To test this, we compared the effect of JQ1 on AR chromatin binding in VCaP cells at AR binding sites co-occupied by BRD4 (denoted AR+BRD4 sites), or AR binding sites not occupied by BRD4 (denoted AR-BRD4 sites, Figure 9A). Whereas AR+BRD4 sites appeared to be higher-affinity AR binding sites than AR-BRD4 sites, JQ1 reduced AR binding by approximately 50% at both of these sub-classes of AR binding sites (Figure 9B). Inspection of specific AR+BRD4 and AR-BRD4 sites (which included FASN-ARBSI and an AR binding site in intron 5 of FKBP5, respectively) confirmed that the presence of H3K27Ac or BET family proteins was not required for JQ1-mediated inhibition of AR binding (Figure 9C and D).
Affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.