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.

Uncovering a superfamily of nickel-dependent hydroxyacid racemases and epimerases

“…Our hypothesis is that D-α-hydroxyacids produced by lactic acid bacteria may have toxic effects in humans and the activity of LarAHs from the microbiome are required for detoxification of these compounds. Two D-α-hydroxyacids have been shown to have adverse effects: D-lactate 31 and D-hydroxyglutarate 32 , and others probably also show toxicity, as D-hydroxyacids are not usual metabolites of eukaryotic cells.…”

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

“…The TME is hypoxic and deprived of critical nutrients that are required for T cell proliferation. In addition, the TME (1) is enriched in metabolic end products that are immunosuppressive, for example, R-2-hydroxyglutarate in tumors with isocitrate dehydrogenase 1/2 mutations; [247][248][249] (2) has increased concentrations of electrolytes, such as potassium, that are immunosuppressive; 250 and (3) harbors reactive oxygen species (ROS) that impair T cell function. 251,252 Several strategies are being actively explored to improve the metabolic function of adoptively transferred T cells.…”

Proteins moonlighting in tumor metabolism and epigenetics

“…Interestingly, in the absence of EGFR/NF1/PTEN mutation, mTORC1/2 signaling is activated by IDH1/2 mutation and exogenous 2-HG, suggesting that 2-HG may regulate the activity of mTOR1/2 through an independent and non-canonical pathway to promote tumor cell survival and proliferation [144,145]. Besides histone and DNA demethylase, more than 60 other α-KG dependent dioxygenases reportedly exist, all of which could be inhibited by 2-HG; these include hypoxia inducible factors (HIF) and AlkB proteins that are responsible for the DNA repair of alkylation damage [146][147][148]. Thus, the oncometabolite 2-HG may Fig.…”