Loss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance
Loss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance
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IRF8 和 AR 之间负反馈环的丢失促进前列腺癌生长和恩杂鲁胺耐药性
DOI：
10.1158/0008-5472.can-19-2549
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发表时间：
2020-07-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Yong
中科院分区：
文献类型：
--
作者：
Wu, Hongxi;You, Linjun;Yang, Yong
在无法治愈的去势抵抗性前列腺癌（CRPC）中，对新型雄激素受体（AR）拮抗剂Enzalutamide的耐药性主要由AR过表达驱动。在这里，我们报告说，干扰素调节因子8（IRF 8）的表达增加，在原发性前列腺癌，但减少CRPC与正常前列腺组织相比。IRF 8表达降低与CRPC进展和Enzalutamide耐药呈正相关。IRF 8与AR相互作用并通过激活泛素/蛋白酶体系统促进其降解。在体外和体内，IRF 8的表观遗传敲低促进AR介导的前列腺癌进展和Enzalutamide耐药。此外，IFN α通过靶向IRF 8-AR轴，增加了IRF 8的表达，并改善了Enzalutamide在CRPC中的疗效。我们还提供了初步证据的疗效IFN α与化疗的临床研究。总的来说，这项研究确定IRF 8既作为前列腺癌发病机制中的肿瘤抑制因子，又作为克服恩杂鲁胺耐药的潜在替代治疗选择。意义：这些发现确定IRF 8介导的AR降解作为对AR靶向治疗的抗性机制，突出了IFN α在CRPC中靶向IRF 8-AR轴的治疗潜力。
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 in vitro and in vivo. Furthermore, IFN alpha increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFN alpha with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance.Significance: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFN alpha in targeting IRF8-AR axis in CRPC.