2. Academic Validation
  3. PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

  • Cell Death Dis. 2024 Jul 23;15(7):524. doi: 10.1038/s41419-024-06920-2.
Ji Wang # 1,  Shiquan Shen # 2,  Jian You # 3,  Zhaotao Wang # 2,  Yan Li 4,  Yanming Chen 5,  Yonghua Tuo 2,  Danmin Chen 2,  Haoming Yu 2,  Jingbo Zhang 2,  Fangran Wang 2,  Xiao Pang 2,  Zongyu Xiao 6,  Qing Lan 7,  Yezhong Wang 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital, Guangzhou Medical University, 510260, Guangzhou, China. neuro-wangji@hotmail.com.
  • 2 Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital, Guangzhou Medical University, 510260, Guangzhou, China.
  • 3 Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 646000, Luzhou, China.
  • 4 Department of Cardiology, The First Affiliated Hospital of University of Science and Technology of China, 230001, Hefei, China.
  • 5 Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China.
  • 6 Department of Neurosurgery, The Fourth Affiliated Hospital of Soochow University, 215124, Suzhou, China. xiaozongyu@hotmail.com.
  • 7 Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 215004, Suzhou, China. szlq006@163.com.
  • 8 Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital, Guangzhou Medical University, 510260, Guangzhou, China. wangyezhong@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 39043634 DOI: 10.1038/s41419-024-06920-2
Abstract

Invasion and migration are the key hallmarks of Cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation MARK (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.

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