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Oncotarget. 2017 Jan 24;8(4):6940-6954. doi: 10.18632/oncotarget.14330.

c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas.

Author information

1
Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.
2
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3
Department of Hematology, Oncology, and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.
4
Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, Sweden.

Abstract

High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

KEYWORDS:

DNMT1; G-CIMP; Glioblastoma; mesenchymal; p-c-Jun

PMID:
28036297
PMCID:
PMC5351681
DOI:
10.18632/oncotarget.14330
[Indexed for MEDLINE]
Free PMC Article

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