PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells

Tianzhi Huang, Yongyong Yang, Xiao Song, Xuechao Wan, Bingli Wu, Namratha Sastry, Craig M. Horbinski, Chang Zeng, Deanna Tiek, Anshika Goenka, Fabao Liu, Cameron W. Brennan, John A. Kessler, Roger Stupp, Ichiro Nakano, Erik P. Sulman, Ryo Nishikawa, Charles David James, Wei Zhang, Wei XuBo Hu*, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

Original languageEnglish (US)
Pages (from-to)1276-1291.e9
JournalMolecular cell
Volume81
Issue number6
DOIs
StatePublished - Mar 18 2021

Keywords

  • CK2
  • GBM
  • GSC
  • PRMT
  • RCC1
  • arginine methylation
  • mitosis
  • phosphorylation
  • therapy response
  • tumorigenicity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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