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Hypoxia Induces Production of L-2-Hydroxyglutarate

2015; Cell Press; Volume: 22; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2015.06.023

1932-7420

Andrew M. Intlekofer, Raymond G. Dematteo, Sriram Venneti, Lydia W.S. Finley, Chao Lü, Alexander R. Judkins, Ariën S. Rustenburg, Patrick Grinaway, John D. Chodera, Justin R. Cross, Craig B. Thompson,

Amino Acid Enzymes and Metabolism

Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the “oncometabolite” D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).