Editors' ChoiceCancer

At the Crossroads: Tumor Metabolism and Epigenetics

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Science Translational Medicine  11 May 2011:
Vol. 3, Issue 82, pp. 82ec68
DOI: 10.1126/scitranslmed.3002597

Do you remember those days of biochemistry, learning cell metabolism basics, such as the Krebs cycle and glycolysis? Now, it is time to relearn them from a different perspective: war on cancer. Isocitrate dehydrogenase 1 (IDH1) in the cytosol and IDH2 in mitochondria catalyze the oxidation of isocitrate to α-ketoglutarate (αKG). Mutations in substrate-binding residues in both IDH1 and IDH2 have been reported in approximately 70% of brain tumors and 15 to 30% of acute myeloid leukemias. These mutations suggest an enzymatic gain-of-function, which catalyzes the reduction of αKG to the R-enantiomer of 2-hydroxyglutarate (R-2HG). Chowdhury et al. now report that accumulation of this oncometabolite, 2HG, probably causes epigenetic changes by inhibiting histone demethylases and by preventing methyl removal from DNA—all of which leads to faulty regulation of gene expression in cancer.

2HG is a competitive inhibitor of several αKG-dependent enzymes, including histone demethylases and DNA hydroxymethylases. The authors reported weak inhibition of the hypoxia-inducible factor (HIF) hydroxylases by 2HG, which suggests that the pathological effects of 2HG are not mediated primarily by direct inhibition of HIF hydroxylases. Posttranslational histone modification is a major mechanism of regulation in gene expression, replication, and repair, and involves a variety of functional group alterations, including methylation. Chowdhury et al. and others showed that for most of the αKG-dependent oxygenases, the S-enantiomer of 2HG was a more potent inhibitor than its R- counterpart. However, for Jumonji histone lysine demethylases, both enantiomers had similar potency.

From a translational medicine point of view, this study is important for several reasons. First, 2HG may be used as a biomarker for disease stratification, minimal residual disease, and relapse in acute myeloid leukemias and brain tumors with IDH mutations. Second, different steps in the new, mutated metabolic pathways can be used as treatment targets. Lastly, cancer cells harboring such mutations possess unique epigenetic signatures; therefore, combination chemotherapies affecting these characteristics might be more effective and less toxic options for cancer patients. From a biochemistry perspective, this study proves that metabolic reprogramming is one of the “hallmarks” of cancer, thus broadening our view of the field beyond our college textbook.

R. Chowdhury et al., The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011). [PubMed]

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