文章：

核糖体S6蛋白激酶4促进胶质母细胞瘤对EZH2抑制剂的耐药性

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma 

原文发布日期：2023-09-19 

英文摘要：

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM. 

摘要翻译： 

胶质母细胞瘤（GBM）是一种高度恶性的脑肿瘤，治疗选择有限。近期研究聚焦于表观遗传调控因子，如Zeste同源物增强子2（EZH2），它通过表观遗传修饰参与基因表达调控。虽然EZH2抑制剂已成为GBM的潜在治疗药物，但其耐药性仍是重大挑战。本研究旨在探讨核糖体S6蛋白激酶4（RSK4）在GBM中的作用及其与EZH2抑制剂耐药性的关联。我们首先通过EZH2抑制剂处理诱导原代GBM细胞系产生耐药性，发现耐药细胞中胶质瘤干细胞（GSCs）相关干性标志物表达升高。在GBM患者样本中观察到RSK4高表达，并发现其与不良预后及GSC标志物表达呈正相关。进一步实验表明，敲低耐药GBM细胞中的RSK4可恢复其对EZH2抑制剂的敏感性，降低GSC标志物表达，从而削弱其自我更新能力。从机制层面，我们发现RSK4直接磷酸化EZH2，激活EZH2/STAT3通路，促进GBM对EZH2抑制剂的耐药性。体外和体内实验均证实，EZH2抑制剂与RSK4抑制剂BI-D1870联用能更有效抑制GBM的发生与发展。本研究揭示RSK4通过不依赖PRC2复合物的方式调控EZH2/STAT3通路，促进GSC维持和EZH2抑制剂耐药性，表明RSK4是GBM治疗的潜在靶点，联合使用EZH2与RSK4抑制剂是一种具有前景的治疗策略。

原文链接：

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma