The effects of 2-hydroxyglutarate on the tumorigenesis of gliomas

• Published in: Contemporary oncology (Poznan, Poland) Vol. 22; no. 4; pp. 215 - 222
• Main Authors: Reiter-Brennan, Cara, Semmler, Lukas, Klein, Andreas
• Format: Journal Article
• Language: English
• Published: Poland Termedia Publishing House 01.01.2018
• Subjects: 2-hydroxyglutarate; Brain cancer; cancer metabolism; epigenome; glioblastoma; Glioma; IDH1 mutation; Metabolism; Review Paper; Tumorigenesis; cancer metabolism; IDH1 mutation; epigenome; 2-hydroxyglutarate; glioblastoma
• ISSN: 1428-2526; 1897-4309
• DOI: 10.5114/wo.2018.82642

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.