biostudies-literatureWu H“Double First-Class” University projectNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationNCI NIH HHSNatural Science Foundation of Jiangsu Province2927-2939https://www.ebi.ac.uk/biostudies/studies/S-EPMC9601976biostudies-literatureUnknown80(13)In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance <i>in vitro</i> and <i>in vivo</i>. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targetiCancer researchLoss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance.PMC9601976CPU2018GY46817727322018M632430R21 CA15335581903656BK2018056081673468CPU2018GF1081672752Duan JDu SYe WBian JZhao ZCheng YZhou JRWu HYou LLi XLi YYang YTao WChen ZShi GGao XWang ZZhu QfalseLoss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance.In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance <i>in vitro</i> and <i>in vivo</i>. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeti2020-01-01T00:00:00Z2020 Jul2025-04-03T21:29:40.011Z2025-04-03T21:29:40.011ZS-EPMC96019763234103710.1158/0008-5472.CAN-19-254910.1158/0008-5472.can-19-2549