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

Academic Article

Abstract

  • © 2014 American Association for Cancer Research. 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.
  • Published In

  • Cancer Discovery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Shim EH; Livi CB; Rakheja D; Tan J; Benson D; Parekh V; Kho EY; Ghosh AP; Kirkman R; Velu S
  • Start Page

  • 1290
  • End Page

  • 1298
  • Volume

  • 4
  • Issue

  • 11