Research Papers:

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

Dieter H. Heiland _, Roberto Ferrarese, Rainer Claus, Fangping Dai, Anie P. Masilamani, Eva Kling, Astrid Weyerbrock, Teresia Kling, Sven Nelander and Maria S. Carro

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Oncotarget. 2017; 8:6940-6954. https://doi.org/10.18632/oncotarget.14330

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Dieter H. Heiland1,2, Roberto Ferrarese1,2, Rainer Claus3, Fangping Dai1,2, Anie P. Masilamani1,2, Eva Kling1,2, Astrid Weyerbrock1,2, Teresia Kling4, Sven Nelander4, Maria S. Carro1,2

1Department of Neurosurgery, Medical Center – University of Freiburg, Freiburg, Germany

2Faculty of Medicine, University of Freiburg, Freiburg, Germany

3Department of Hematology, Oncology, and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany

4Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, Sweden

Correspondence to:

Maria S. Carro, email: [email protected]

Keywords: Glioblastoma, G-CIMP, DNMT1, p-c-Jun, mesenchymal

Received: June 11, 2016    Accepted: December 15, 2016    Published: December 28, 2016


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.

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