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

Mol Cell. 2021 Mar 18;81(6):1276-1291.e9. doi: 10.1016/j.molcel.2021.01.015. Epub 2021 Feb 3.

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.

Keywords: CK2; GBM; GSC; PRMT; RCC1; arginine methylation; mitosis; phosphorylation; therapy response; tumorigenicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / radiotherapy
  • Carcinogenesis* / genetics
  • Carcinogenesis* / metabolism
  • Carcinogenesis* / radiation effects
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Line, Tumor
  • Female
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / radiotherapy
  • Guanine Nucleotide Exchange Factors* / genetics
  • Guanine Nucleotide Exchange Factors* / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mitosis / genetics
  • Mitosis / radiation effects*
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Protein-Arginine N-Methyltransferases* / genetics
  • Protein-Arginine N-Methyltransferases* / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / radiation effects
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Neoplasm Proteins
  • Nuclear Proteins
  • RCC1 protein, human
  • PRMT6 protein, human
  • Protein-Arginine N-Methyltransferases
  • Casein Kinase II