Loss of a negative feedback loop between IRF8 and AR promotes prostate cancer growth and enzalutamide resistance | Cancer Research

Loss of a negative feedback loop between IRF8 and AR promotes prostate cancer growth and enzalutamide resistance | Cancer Research: In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide (ENZ) is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer (PCa) but decreased in CRPC compared to normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and ENZ resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated PCa progression and ENZ resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of ENZ in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in PCa pathogenesis and a potential alternative therapeutic option to overcome ENZ resistance.