IDH1(R132H) Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells

The R132H mutation in isocitrate dehydrogenase 1 (IDH1(R132H)) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1(R132H) as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1(R132H) suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1(R132H)-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1(R132H) and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1(R132H)-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1(R132H), significantly attenuates HDACi resistance and NANOG expression IDH1(R132H)-expressing glioblastoma cells. These results suggested that IDH1(R132H) is a potential molecular target for HDACi-based therapy for GBM.