Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Theranostics. 2021 Mar 4;11(10):4809-4824. doi: 10.7150/thno.55814. eCollection 2021.
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. 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, and . The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). 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 and . 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. 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.
晚期前列腺癌（PCa）的治疗方案有限，对化疗和免疫治疗的反应较低，导致预后不良。组蛋白修饰是基因表达的重要机制，也是有前途的治疗靶点。在这项研究中，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。
我们基于 TCGA 数据对特定的组蛋白修饰调节剂进行了表征。在两个独立的队列中分析了 WDR5 的表达和临床特征。我们进一步通过 siRNA 和 WDR5 的小分子拮抗剂 OICR-9429 以及 OICR-9429 来研究 WDR5 的功能作用。通过 RNA-seq 和染色质免疫沉淀（ChIP）来探索 WDR5 的机制。
WDR5 在 PCa 中过表达，与晚期临床病理特征相关，并预测预后不良。siRNA 和 OICR-9429 抑制 WDR5 均可降低增殖，增加凋亡，并提高顺铂和 IFN-γ的化疗敏感性。有趣的是，siRNA 和 OICR-9429 靶向 WDR5 可阻断 PCa 细胞中 IFN-γ诱导的 PD-L1 表达。从机制上讲，我们阐明了一些细胞周期、抗凋亡、DNA 修复和免疫相关基因，包括 AURKA、CCNB1、E2F1、PLK1、BIRC5、XRCC2 和 PD-L1，它们直接受 WDR5 和 OICR-9429 调控，依赖于 H3K4me3 和 c-Myc。
这些数据表明，靶向 WDR5 可抑制 PCa 的增殖，增强凋亡，提高顺铂和免疫治疗的敏感性。因此，我们的研究结果表明，OICR-9429 是一种多功能且有前途的治疗药物，可提高顺铂或免疫治疗在 PCa 中的抗肿瘤效果。
