| 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. © 2021 Elsevier Inc. Huang et al. show that PRMT6 methylates RCC1 at arginine 214, which is required for RCC1 association with chromatin and activation of RAN. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation. Inhibition of PRMT6 reduces tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice. © 2021 Elsevier Inc. |
