L-2-hydroxyglutarate: An epigenetic modifier and putative oncometabolite in renal cancer

Eun Hee Shim, Carolina B. Livi, Dinesh Rakheja, Jubilee Tan, Daniel Benson, Vishwas Parekh, Eun Young Kho, Arindam P. Ghosh, Richard Kirkman, Sadanan Velu, Shilpa Dutta, Balachandra Chenna, Shane L. Rea, Robert J. Mishur, Qiuhua Li, Teresa L. Johnson-Pais, Lining Guo, Sejong Bae, Shi Wei, Karen BlockSunil Sudarshan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1290-1298
Number of pages9
JournalCancer discovery
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2014

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ASJC Scopus subject areas

  • Oncology

Cite this

Shim, E. H., Livi, C. B., Rakheja, D., Tan, J., Benson, D., Parekh, V., Kho, E. Y., Ghosh, A. P., Kirkman, R., Velu, S., Dutta, S., Chenna, B., Rea, S. L., Mishur, R. J., Li, Q., Johnson-Pais, T. L., Guo, L., Bae, S., Wei, S., ... Sudarshan, S. (2014). L-2-hydroxyglutarate: An epigenetic modifier and putative oncometabolite in renal cancer. Cancer discovery, 4(11), 1290-1298. https://doi.org/10.1158/2159-8290.CD-13-0696