PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.
Mol Cell
; 81(6): 1276-1291.e9, 2021 03 18.
Article
em En
| MEDLINE
| ID: mdl-33539787
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.
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MEDLINE
Assunto principal:
Proteína-Arginina N-Metiltransferases
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Neoplasias Encefálicas
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Proteínas Nucleares
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Glioblastoma
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Proteínas de Ciclo Celular
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Fatores de Troca do Nucleotídeo Guanina
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Carcinogênese
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Mitose
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article