Journal
CANCER DISCOVERY
Volume 4, Issue 11, Pages 1290-1298Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0696
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Funding
- NIH [P30 CA013148, K08 CA138774, R01 NCI CA131272]
- Urology Care Foundation
- Astellas Pharrna Rising Star Award
- American Cancer Society [RSG-12-127-01 CNE]
- Clinical & Translational Science Awards/Institute for Integration of Medicine and Science [UL1RR025767]
- Cancer Prevention Research Institute of Texas [RP120190]
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Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors. In contrast, kidney tumors demonstrate elevations of the l enantiomer of 2HG (l-2HG). High-2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC), consistent with 2HG-mediated inhibition of ten-eleven translocation (TET) enzymes, which convert 5-methylcytosine (5mC) to 5hmC. l-2HG elevation is mediated in part by reduced expression of l-2HG dehydrogenase (L2HGDH). L2HGDH reconstitution in RCC cells lowers l-2HG and promotes 5hmC accumulation. In addition, L2HGDH expression in RCC cells reduces histone methylation and suppresses in vitro tumor phenotypes. Our report identifies l-2HG as an epigenetic modifier and putative oncometabolite in kidney cancer.
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