title: c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas.
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.
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Dieter H
authors.initials: DH
authors.lastname: Heiland
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrarese
authors.affiliation: Department of Hematology, Oncology, and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Fangping
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Anie P
authors.initials: AP
authors.lastname: Masilamani
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kling
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.affiliation: Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, Sweden.
authors.forename: Teresia
authors.initials: T
authors.lastname: Kling
authors.affiliation: Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Carro
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D000841:Anisomycin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human
keywords: DNMT1; G-CIMP; Glioblastoma; mesenchymal; p-c-Jun