D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth

Oncotarget. 2015 Apr 20;6(11):8606-20. doi: 10.18632/oncotarget.3330.

Abstract

Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.

Keywords: D-2-HG; D2HGDH; IDH mutation; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Division
  • Cell Line, Tumor
  • Cell Movement
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Glutarates / metabolism*
  • Heterografts
  • Humans
  • Isocitrate Dehydrogenase / deficiency
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / physiology*
  • Ketoglutaric Acids / antagonists & inhibitors
  • Male
  • Mice
  • Mice, Nude
  • Mitochondria / metabolism
  • Mixed Function Oxygenases / metabolism
  • Mutation, Missense
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Sarcoma / genetics
  • Sarcoma / metabolism
  • Sarcoma / pathology*
  • Transfection

Substances

  • Glutarates
  • Ketoglutaric Acids
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • alpha-hydroxyglutarate
  • Mixed Function Oxygenases
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human