Dong Feng, Cheng Xuan, Wan Jiaxiang, Li Qian, Du Weijian, Li Wei, Sun Xiaoyu, Wu Xudong
State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Medical Epigenetics, School of Biomedical Engineering & Technology, Tianjin Medical University, Tianjin, 300070, China.
Department of Cell Biology, Tianjin Medical University, Tianjin, 300070, China.
Sci China Life Sci. 2025 Sep 5. doi: 10.1007/s11427-025-2959-x.
Histone arginine methylation by protein arginine methyltransferases (PRMTs) is crucial for transcriptional regulation and is implicated in cancers. Despite their therapeutic potential, some PRMTs present challenges as drug targets due to their context-dependent activities. Here, we demonstrate that hypoxia triggers the rapid condensation of PRMT2, which is essential for its histone H3R8 asymmetric dimethylation (H3R8me2a) activity. This process depends on PRMT2's integration into transcriptional condensates, which is mediated by phosphorylation at Serine 12 within its N-terminal intrinsically disordered region. This phosphorylation is critical for hypoxia-inducible gene expression and glioblastoma (GBM) progression. Transcription-associated cyclin-dependent kinases (CDKs), particularly CDK9, drive PRMT2S12 phosphorylation. Inhibition of CDK9 using TG02 suppresses hypoxia-induced H3R8me2a and transcriptional activity. Moreover, the combination of TG02 and temozolomide, the standard chemotherapy for GBM, significantly inhibits tumor progression in mouse xenograft models, an effect partially mediated by targeting PRMT2S12 phosphorylation. Our study uncovers the role of transcriptional condensation in enhancing PRMT activity, reveals a new mechanism for CDK9 inhibitors in modulating context-dependent transcriptional programs, and proposed a combinatorial therapeutic strategy against GBM.
蛋白质精氨酸甲基转移酶（PRMTs）介导的组蛋白精氨酸甲基化对于转录调控至关重要，并且与癌症相关。尽管它们具有治疗潜力，但由于其活性依赖于上下文，一些PRMTs作为药物靶点存在挑战。在这里，我们证明缺氧会触发PRMT2的快速凝聚，这对其组蛋白H3R8不对称二甲基化（H3R8me2a）活性至关重要。这个过程取决于PRMT2整合到转录凝聚物中，这是由其N端内在无序区域的丝氨酸12磷酸化介导的。这种磷酸化对于缺氧诱导的基因表达和胶质母细胞瘤（GBM）进展至关重要。转录相关的细胞周期蛋白依赖性激酶（CDKs），特别是CDK9，驱动PRMT2 S12磷酸化。使用TG02抑制CDK9可抑制缺氧诱导的H3R8me2a和转录活性。此外，TG02与GBM的标准化疗药物替莫唑胺联合使用，可显著抑制小鼠异种移植模型中的肿瘤进展，这种作用部分是通过靶向PRMT2 S12磷酸化介导的。我们的研究揭示了转录凝聚在增强PRMT活性中的作用，揭示了CDK9抑制剂调节上下文依赖性转录程序的新机制，并提出了一种针对GBM的联合治疗策略。
