c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, 6940-6954 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2017. Vol. 8, no 4, 6940-6954 p.
Glioblastoma, G-CIMP, DNMT1, p-c-Jun, mesenchymal
Cancer and Oncology Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-317698DOI: 10.18632/oncotarget.14330ISI: 000393289000125PubMedID: 28036297OAI: oai:DiVA.org:uu-317698DiVA: diva2:1082661
FunderGerman Research Foundation (DFG), CA 1246/2-1