The androgen receptor (AR) remains the primary molecular target for prostate cancer (PCa) treatment and for development of novel therapies. Profiling and other analyses of human prostate adenocarcinoma have shown that the AR is still functional during late-stage disease in the absence of circulating hormone following castration therapy. The molecular mechanisms that operate during this ‘castration resistant’ phase are still not well understood. Qi et al. have now implicated the ubiquitin ligase Siah2 as an important mediator of AR action in castration resistant prostate cancer (CRPC). Siah2 was found to target repressed AR chromatin complexes for degradation, resulting in activation of AR-regulated genes involved in tumor cell proliferation, cell motility and lipid metabolism. The authors show a requirement for Siah2 activity for PCa cell growth under conditions of low androgen, and also that targeting Siah2 results in tumor growth suppression under castrate conditions. These findings identify a new mechanism of AR regulation in progressing disease as well as a novel enzymatic target for therapeutic intervention.

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