anisomycin and Brain-Neoplasms

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.

Topics: Anisomycin; Brain Neoplasms; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Genome, Human; Glioma; Humans; Phosphorylation; Prognosis; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun; Survival Analysis; Up-Regulation

The effects of protein synthesis inhibitors (cycloheximide, anisomycin, puromycin and emetine) on the growth of human brain tumor cells were investigated using U-373 MG human astrocytoma and SK-N-MC human neuroblastoma cell lines. These agents inhibited the growth of the tumor cells in a dose-dependent manner. However, these agents did not affect cell viability evaluated by the trypan blue exclusion method, indicating that growth inhibition was due to the inhibition of cell proliferation rather than the induction of cytotoxicity. Anti-proliferation induced by these agents was significantly blocked by the treatments with either free radical scavengers or antioxidants. These results suggest that enhanced oxidative stress may be involved in the anti-proliferation induced by the protein synthesis inhibitors in human brain tumor cells.

Topics: Anisomycin; Astrocytoma; Brain Neoplasms; Cell Division; Cycloheximide; Drug Screening Assays, Antitumor; Emetine; Humans; Neuroblastoma; Protein Synthesis Inhibitors; Puromycin; Tumor Cells, Cultured