Abstract
Small-molecule inhibitors of BET family proteins retard progression of AR-dependent CRPC.
Major finding: Small-molecule inhibitors of BET family proteins retard progression of AR-dependent CRPC.
Concept: BET family proteins bind to AR and drive expression of many AR-dependent genes.
Impact: Inhibitors of BET family proteins should be clinically evaluated for treatment of CRPC.
Over half of patients with castration-resistant prostate cancer (CRPC) develop resistance to hormonal therapies as a result of androgen receptor (AR) amplification, mutation, or alternative splicing, which serve to maintain AR signaling. Although therapies directly targeting AR activity can temporarily restrain disease, CRPC frequently evolves resistance to such agents, necessitating a continued search for alternative therapeutic approaches. Asangani and colleagues evaluated the activity of JQ1, an inhibitor of the bromodomain extra terminal (BET) family protein bromodomain-containing protein 4 (BRD4) that shows antiproliferative effects in other cancers, in prostate cancer cell lines. JQ1 had no effect on AR signaling-negative lines, but induced cell-cycle arrest and apoptosis and suppressed AR target gene expression in AR-positive lines, suggesting that BRD4 may be involved in AR signaling. Microarray analysis of JQ1-treated cells demonstrated that BRD4 was required for expression of many AR target genes, among them ETS-related gene (ERG), a major oncogenic driver of prostate cancer. Because BRD4 is a chromatin adaptor with known transcription factor binding partners, this finding raised the possibility that BRD4 may physically interact with AR to regulate gene expression. Indeed, gel filtration chromatography studies showed that BRD4 directly bound to AR, forming a multiprotein complex that also included RNA polymerase II, and genome-wide chromatin immunoprecipitation showed that BRD4 and AR were corecruited to AR-regulated genes. JQ1 and another BET family inhibitor, I-BET762, disrupted the interaction between AR and BRD4 and inhibited androgen-mediated AR recruitment to AR target genes, including ERG. Further, in preclinical studies JQ1 suppressed development of CRPC cell xenografts in mice and prevented metastasis, whereas the competitive AR inhibitor enzalutamide actually promoted metastasis. Together, these data demonstrate that BRD4 is an important mediator of AR-driven prostate cancer and suggest that BET family inhibitors may be useful in treatment of CRPC.
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