IDH1-R132H mutation radiosensitizes U87MG glioma cells via epigenetic downregulation of TIGAR
Abstract
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in World Health Organization grade II-III gliomas and secondary gliomas. The majority of IDH1 mutations involve a substitution of arginine to histidine at codon 132 (IDH1-R132H). While the oncogenic role of IDH1-R132H is well established, patients with IDH1-R132H mutations tend to respond better to radiotherapy than those with wild-type (WT) IDH1. This study explores the potential mechanism behind the radiosensitizing effects of IDH1-R132H by overexpressing IDH1-R132H in U87MG glioma cells. The findings showed that IDH1-R132H-expressing cells had a reduced clonogenic survival rate and exhibited delayed DNA double-strand break repair compared to cells with IDH1-WT. Analysis of data from The Cancer Genome Atlas revealed that expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) was lower in glioma patients with IDH1 mutations compared to those with IDH1-WT. Knockdown of TIGAR enhanced glioma cell radiosensitivity, and in U87MG cells, IDH1-R132H was found to suppress TIGAR expression. Chromatin immunoprecipitation assays showed increased repressive H3K9me3 modifications at the TIGAR promoter in IDH1-R132H cells compared to IDH1-WT cells. These results suggest that IDH1-R132H may contribute to overcoming GSK864 radioresistance in glioma cells through epigenetic repression of TIGAR expression. However, this effect was not observed in U87MG glioma stem-like cells. This study provides deeper insights into the role of IDH1 mutations in glioma, which could help enhance the effectiveness of radiotherapy.