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.

JNK Pathway Mediates Low Oxygen Level Induced Epithelial–Mesenchymal Transition and Stemness Maintenance in Colorectal Cancer Cells

“…The JNK pathway is a possible delayed pathway that is activated in 10% O 2 in light of our previous study [14]. Also, there was research showing that JNK signaling may contribute to Snail and TWIST1 activation by DNA methyltransferase 1 (DNMT1) or TGF-β1-induced EMT pathway by promoting fibronectin and vimentin [21][22][23][24][25][26][27]. Our results demonstrated the general activation through hyperphosphorylation under low oxygen levels among all three cell lines, and this confirmed the activation of JNK pathway among CRCs.…”

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

“…In recent work with murine cells, oncogenic Ras signaling has been shown to induce transcriptional changes leading to an accumulation of H3K27me3 and to mediate upregulation of Dnmt1 and Dnmt3a expression, which provides a molecular link for RAS-mediated transcriptional silencing and DNA hypermethylation 45 – 47 . Furthermore, it has been shown that phosphorylated c-Jun, which is regulated in a RAS-dependent manner, upregulates DNMT1 expression and causes DNA hypermethylation 48 . Oncogenic KRAS is also able to suppress the expression of TET1 in an ERK-dependent manner, thereby contributing to DNA hypermethylation 32 .…”

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

“…In earlier studies, JNK phosphorylation is found to mediate TGF-β1-induced EMT by promoting fibronectin and vimentin synthesis in fibroblasts and keratinocytes (114)(115)(116). Additionally, JNK activation of the proliferating cell nuclear antigen (PCNA) and DNA methyltransferase 1 associated protein 1 (DMAP1) domains of DNA methyltransferase 1 (DNMT1) can directly interact with Snail and suppress E-cadherin in colorectal cancer, glioma, and nasopharyngeal carcinoma cell lines (117)(118)(119). Furthermore, JNK may be associated with Snail and TWIST1 via c-Jun in multi-drug resistant epidermoid carcinoma and as a downstream effector of Akt in gastric cancer cells (120,121).…”