WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer.
WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer.
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WD 重复结构域 5 促进前列腺癌中的化疗耐药性和程序性死亡配体 1 的表达。
DOI：
10.7150/thno.55814
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Zhou Q;Chen X;He H;Peng S;Zhang Y;Zhang J;Cheng L;Liu S;Huang M;Xie R;Lin T;Huang J
目的：晚期前列腺癌（PCa）治疗方案有限，对化疗和免疫治疗反应较低，预后较差。组蛋白修饰是一种重要的基因表达机制，也是一种很有前景的治疗靶点。在本研究中，我们对组蛋白修饰的调节因子WD重复结构域5 （WDR5）进行了表征，并探讨了其在PCa中的潜在治疗价值。实验设计：基于TCGA数据，我们描述了组蛋白修饰的特定调节因子。在两个依赖队列中分析WDR5的表达和临床特征。利用siRNA和WDR5的小分子拮抗剂OICR-9429在体外和体内进一步研究WDR5的功能作用。通过rna测序和染色质免疫沉淀（ChIP）技术探讨WDR5的作用机制。结果：WDR5在PCa中过表达，与晚期临床病理特征相关，预测预后不良。体外和体内实验中，siRNA和OICR-9429抑制WDR5均能抑制细胞增殖，增加细胞凋亡和对顺铂的化疗敏感性。有趣的是，通过siRNA和OICR-9429靶向WDR5可以阻断IFN-γ诱导的PD-L1在PCa细胞中的表达。在机制上，我们明确了一些细胞周期、抗凋亡、DNA修复和免疫相关基因，包括AURKA、CCNB1、E2F1、PLK1、BIRC5、XRCC2和PD-L1，是由WDR5和OICR-9429以依赖H3K4me3和c-Myc的方式直接调控的。结论：这些数据表明，靶向WDR5可抑制前列腺癌的增殖，增强细胞凋亡，对顺铂和免疫治疗的化疗敏感性。因此，我们的研究结果揭示了OICR-9429是一种多效且有前景的治疗药物，可以提高顺铂或免疫治疗在PCa中的抗肿瘤效果。
Purpose: Advanced prostate cancer (PCa) has limited treatment regimens and shows low response to chemotherapy and immunotherapy, leading to poor prognosis. Histone modification is a vital mechanism of gene expression and a promising therapy target. In this study, we characterized WD repeat domain 5 (WDR5), a regulator of histone modification, and explored its potential therapeutic value in PCa. Experimental Design: We characterized specific regulators of histone modification, based on TCGA data. The expression and clinical features of WDR5 were analyzed in two dependent cohorts. The functional role of WDR5 was further investigated with siRNA and OICR-9429, a small molecular antagonist of WDR5, in vitro and in vivo. The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). Results: WDR5 was overexpressed in PCa and associated with advanced clinicopathological features, and predicted poor prognosis. Both inhibition of WDR5 by siRNA and OICR-9429 could reduce proliferation, and increase apoptosis and chemosensitivity to cisplatin in vitro and in vivo. Interestingly, targeting WDR5 by siRNA and OICR-9429 could block IFN-γ-induced PD-L1 expression in PCa cells. Mechanistically, we clarified that some cell cycle, anti-apoptosis, DNA repair and immune related genes, including AURKA, CCNB1, E2F1, PLK1, BIRC5, XRCC2 and PD-L1, were directly regulated by WDR5 and OICR-9429 in H3K4me3 and c-Myc dependent manner. Conclusions: These data revealed that targeting WDR5 suppressed proliferation, enhanced apoptosis, chemosensitivity to cisplatin and immunotherapy in PCa. Therefore, our findings provide insight into OICR-9429 is a multi-potency and promising therapy drug, which improves the antitumor effect of cisplatin or immunotherapy in PCa.
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