2. Academic Validation
  3. Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma

Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma

  • Sci China Life Sci. 2025 Sep 5. doi: 10.1007/s11427-025-2959-x.
Feng Dong # 1 2,  Xuan Cheng # 3,  Jiaxiang Wan 2,  Qian Li 2,  Weijian Du 2,  Wei Li 4,  Xiaoyu Sun 2,  Xudong Wu 5 6 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cell Biology, Tianjin Medical University, Tianjin, 300070, China.
  • 3 Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 4 Department of Pathology, Tianjin First Central Hospital, Tianjin, 300192, China.
  • 5 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. wuxudong@tmu.edu.cn.
  • 6 Department of Cell Biology, Tianjin Medical University, Tianjin, 300070, China. wuxudong@tmu.edu.cn.
  • 7 Department of Neurosurgery, Tianjin Medical University General Hospital and Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China. wuxudong@tmu.edu.cn.
  • # Contributed equally.
PMID: 40926175 DOI: 10.1007/s11427-025-2959-x
Abstract

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.

Keywords

PRMT2; glioblastoma; hypoxia; transcriptional condensate; transcriptional cyclin-dependent kinases.

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