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

Heiland, Dieter H.Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)

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.

Ferrarese, RobertoUniv Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Claus, RainerUniv Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany. (författare)
Dai, FangpingUniv Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Masilamani, Anie P.Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Kling, EvaUniv Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Weyerbrock, AstridUniv Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Kling, TeresiaUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab (författare)
Nelander, SvenUppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)svene843 (författare)
Carro, Maria S.Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany. (författare)
Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany.Univ Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany. (creator_code:org_t)

Av författaren/redakt...: Heiland, Dieter ...; Ferrarese, Rober ...; Claus, Rainer; Dai, Fangping; Masilamani, Anie ...; Kling, Eva; visa fler...; Weyerbrock, Astr ...; Kling, Teresia; Nelander, Sven; Carro, Maria S.; visa färre...

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