IDH mutation–derived R-2HG impels tumor growth by driving metabolism and apoptosis resistance.
Major finding: IDH mutation–derived R-2HG impels tumor growth by driving metabolism and apoptosis resistance.
Mechanism: R-2HG–mediated hypersuccinylation causes mitochondrial dysfunction and BCL2 accumulation.
Impact: Inhibition of hypersuccinylation is a potential therapeutic strategy for IDH-mutant tumors.
Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, which have been identified in multiple tumor types including gliomas, result in the reduction of α-ketoglutarate (α-KG) to the α-KG analogue (R)-2-hydroxyglutarate (R-2HG) and are associated with a hypermethylator phenotype. However, inhibition of R-2HG production results in a decrease in tumor growth but does not affect methylation levels. To ascertain how R-2HG accumulation promotes tumorigenicity, Li, He, Ye and colleagues investigated the role of R-2HG in succinylation, a common posttranslational lysine modification involving succinyl-CoA, which is converted into succinate in the tricarboxylic acid (TCA) cycle. In vitro studies revealed that R-2HG competitively inhibited the TCA cycle enzyme succinate dehydrogenase (SDH), which catalyzes the oxidation of succinate to fumarate in IDH1-mutant cells, leading to significantly increased levels of succinate. Furthermore, inactivation of SDH, treatment with a membrane-permeable R-2HG ester, or expression of R-2HG–producing IDH1 mutations in glioma cells resulted in increased succinyl-CoA levels and preferentially induced hypersuccinylation of mitochondrial proteins. Similarly, hypersuccinylation was present in IDH1-mutant gliomas from patients, most prominently in the mitochondria. Hypersuccinylation induced by a mutant IDH1 or knockdown of the desuccinylase sirtuin 5 (SIRT5) resulted in increased histone methylation and decreased activity of metabolism-related enzymes. Mechanistically, IDH mutation–induced hypersuccinylation increased tumor metabolism by driving mitochondrial depolarization and inhibiting mitochondrial respiration, and promoted apoptosis resistance by inducing localization of BCL2 to the mitochondrial membrane. SIRT5 overexpression or glycine supplementation resulted in decreased succinylation, increased sensitivity to apoptosis, and diminished growth of glioma. Together, these results show that IDH mutant–derived R-2HG promotes tumorigenic increases in metabolism and apoptosis resistance by inducing hypersuccinylation, which represents a potential therapeutic target for hypersuccinylation-related tumors.
- ©2015 American Association for Cancer Research.