PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.
Animals
Brain Neoplasms
/ genetics
Carcinogenesis
/ genetics
Casein Kinase II
/ genetics
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
Female
Glioblastoma
/ genetics
Guanine Nucleotide Exchange Factors
/ genetics
HEK293 Cells
Humans
Male
Mice
Mitosis
/ genetics
Neoplasm Proteins
/ genetics
Nuclear Proteins
/ genetics
Protein-Arginine N-Methyltransferases
/ genetics
Signal Transduction
/ genetics
Xenograft Model Antitumor Assays
CK2
GBM
GSC
PRMT
RCC1
arginine methylation
mitosis
phosphorylation
therapy response
tumorigenicity
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 03 2021
18 03 2021
Historique:
received:
02
06
2020
revised:
02
11
2020
accepted:
11
01
2021
pubmed:
5
2
2021
medline:
2
4
2021
entrez:
4
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33539787
pii: S1097-2765(21)00015-0
doi: 10.1016/j.molcel.2021.01.015
pmc: PMC7979509
mid: NIHMS1664461
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Guanine Nucleotide Exchange Factors
0
Neoplasm Proteins
0
Nuclear Proteins
0
RCC1 protein, human
0
PRMT6 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Casein Kinase II
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1276-1291.e9Subventions
Organisme : NINDS NIH HHS
ID : R01 NS095642
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201402
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102669
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234799
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS093843
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA232630
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236356
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS117104
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213293
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054429
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095634
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA209345
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115403
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS107071
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001422
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors, and their immediate family members, are not members of the Molecular Cell advisory board. The authors declare no further competing interests.
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