<scp>l</scp> -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer

Eun‐Hee Shim(University of Alabama at Birmingham), Carolina B. Livi(The University of Texas at San Antonio Health Science Center), Dinesh Rakheja(The University of Texas Southwestern Medical Center), Jubilee Tan(University of Alabama at Birmingham), Daniel Benson(University of Alabama at Birmingham), Vishwas Parekh(University of Alabama at Birmingham), Eun-Young Kho(University of Alabama at Birmingham), Arindam Ghosh(University of Alabama at Birmingham), Richard Kirkman(University of Alabama at Birmingham), Sadanandan E. Velu(University of Alabama at Birmingham), Shilpa Dutta(University of Alabama at Birmingham), Balachandra Chenna(University of Alabama at Birmingham), Shane L. Rea(The University of Texas at San Antonio Health Science Center), Robert J. Mishur(The University of Texas at San Antonio Health Science Center), Qiuhua Li(The University of Texas at San Antonio Health Science Center), Teresa L. Johnson‐Pais(The University of Texas at San Antonio Health Science Center), Lining Guo(Metabolon (United States)), Sejong Bae(University of Alabama at Birmingham), Shi Wei(University of Alabama at Birmingham), Karen Block(The University of Texas at San Antonio Health Science Center), Sunil Sudarshan(University of Alabama at Birmingham)
Cancer Discovery
September 3, 2014
10.1158/2159-8290.cd-13-0696
Cited by 294Open Access
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Abstract

UNLABELLED: 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. SIGNIFICANCE: Here, we report elevations of the putative oncometabolite l-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer.

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