The effects of 2-hydroxyglutarate on the tumorigenesis of gliomas

Abstract

Mutation of the isocitrate-dehydrogenase (IDH) enzymes is one of the central research topics regarding gliomagenesis. Indeed, 70% of gliomas are associated with a gain-of-function IDH mutation and consequently synthesize the oncometabolite, 2-hydroxyglutarate (2-HG). This review aims to elucidate the effects of 2-HG on gliomagenesis. 2-HG promotes tumorigenesis by impacting metabolism, vascularization and altering the epigenome of glioma cells. Glioma metabolism and vascularization is altered by 2-HG's effect on the stability of hypoxia-inducible factor (HIF) and inhibition of endostatin. However, 2-HG's impacts on epigenetic mechanisms are more profound to gliomagenesis. Through competitive inhibition of JHDMs and TET proteins, 2-HG orchestrates histone and DNA hypermethylation, which is associated with gene silencing and dedifferentiation of cells. The hypermethylator phenotype induced by 2-HG also results in alterations of the interaction of the immune system with the tumour. Additionally, this study reviews 2-HG promotion of tumorigenesis by inhibiting repair of DNA alkylation damage through competitive inhibition of AlkB proteins.

Keywords: 2-hydroxyglutarate; IDH1 mutation; cancer metabolism; epigenome; glioblastoma.

Fig. 1

In physiological conditions, IDH1/2 metabolizes isocitrate to a-KG with the production of NADPH and CO2. Cancerous mutated IDH1/2 synthesizes 2-HG and NADP+ from a-KG. 2-HG competitively inhibits numerous a-KG-dependent-dixoxygenases. Here illustrated is 2-HG‘s competitive inhibition of JHDMs and TET1/2, which results in histone and DNA methylation, respectively. 2-HG also inhibits ALKBHs, leading to less DNA repair of methylation damage. Overall, these effects induced by 2-HG alter the epigenome of glioma cells and promote tumorigenesis Isocitrate

Fig. 2

2-hydroxyglutarate (2-HG) is a chiral molecule, which exists in a L-(S)-2-HG and D-(R)-2-HG form. In cancers, mutated IDH1/2 generates almost exclusively D-(R)-2-HG from α-ketoglutarate (α-KG). L-(S)-2-HG is synthesised during hypoxic conditions through lactatedehydrogenase A (LDHA) and malatedehydrogenase (MDH1/2)