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

Heiland DH, Ferrarese R, Claus R, Dai F, Masilamani AP, Kling E, Weyerbrock A, Kling T, Nelander S, Carro MS

Oncotarget 8 (4) 6940-6954 [2017-01-24; online 2016-12-31]

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.

Affiliated researcher

PubMed 28036297

DOI 10.18632/oncotarget.14330

Crossref 10.18632/oncotarget.14330

pii: 14330
pmc: PMC5351681

Publications 9.5.0