Inhibition of enhancer of zeste homolog 2 (EZH2) overcomes enzalutamide resistance in castration-resistant prostate cancer
Inhibition of enhancer of zeste homolog 2 (EZH2) overcomes enzalutamide resistance in castration-resistant prostate cancer
复制标题
抑制zeste增强子同源物2（EZH2）克服去势抵抗性前列腺癌中的恩杂鲁胺耐药性
DOI：
10.1074/jbc.ra119.008152
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发表时间：
2019-06-21
影响因子：
4.8
通讯作者：
Liu, Xiaoqi
中科院分区：
文献类型：
--
作者：
Bai, Yunfeng;Zhang, Zhuangzhuang;Liu, Xiaoqi
Enzalutamide于2018年获得美国食品药品监督管理局批准用于治疗转移性去势抵抗性前列腺癌（CRPC），是一种雄激素受体（AR）抑制剂。它阻断雄激素与AR结合、AR核转位和AR介导的DNA结合。不幸的是，相当大比例的肿瘤最终在治疗过程中产生耐药性。Enzalutamide耐药的分子机制尚未完全了解。Zeste增强子同源物2（EZH 2）是多梳阻遏复合物2的催化亚基，已被提议作为前列腺癌（PCa）的预后标志物。为了测试EZH 2是否也在CRPC中获得恩杂鲁胺耐药性中起关键作用，我们在此检查了EZH 2抑制/消耗是否增强恩杂鲁胺在恩杂鲁胺耐药性PCa细胞中的疗效。我们发现，EZH 2抑制剂GSK 126与恩杂鲁胺的组合协同抑制细胞增殖和集落形成，并促进恩杂鲁胺耐药PCa细胞的凋亡。EZH 2耗竭还克服了培养细胞和异种移植肿瘤中的恩杂鲁胺抗性。从机制上讲，我们发现EZH 2直接与前列腺特异性抗原的启动子结合，并抑制其在恩杂鲁胺耐药PCa细胞中的表达。与此一致，涉及GSEA的临床RNA测序数据的生物信息学分析表明，在PCa进展期间AR和EZH 2基因表达之间存在强相关性。我们的研究为Enzalutamide耐药的潜在机制提供了重要的见解，这可能为增强Enzalutamide在CRPC中的疗效提供新的方法。
Enzalutamide, approved by the United States Food and Drug Administration in 2018 for the management of metastatic castration-resistant prostate cancer (CRPC), is an androgen receptor (AR) inhibitor. It blocks androgen binding to the AR, AR nuclear translocation, and AR-mediated DNA binding. Unfortunately, a considerable proportion of tumors eventually develop resistance during the treatment. The molecular mechanisms underlying enzalutamide resistance are not completely understood. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressor complex 2, has been proposed as a prognostic marker for prostate cancer (PCa). With the goal to test whether EZH2 also plays a critical role in acquisition of enzalutamide resistance in CRPC, here we examined whether EZH2 inhibition/depletion enhances the efficacy of enzalutamide in enzalutamide-resistant PCa cells. We show that combining the EZH2 inhibitor GSK126 with enzalutamide synergistically inhibits cell proliferation and colony formation and promotes apoptosis in enzalutamide-resistant PCa cells. EZH2 depletion also overcomes enzalutamide resistance in both cultured cells and xenograft tumors. Mechanistically, we found that EZH2 directly binds to the promoter of prostate-specific antigen and inhibits its expression in enzalutamide-resistant PCa cells. In agreement, bioinformatics analysis of clinical RNA sequencing data involving GSEA indicated a strong correlation between AR and EZH2 gene expression during PCa progression. Our study provides critical insights into the mechanisms underlying enzalutamide resistance, which may offer new approaches to enhance the efficacy of enzalutamide in CRPC.