Oncometabolite in Renal Cancer
2014
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 which 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 2-HG mediated inhibition of TET (Ten Eleven Translocation) enzymes which convert 5-methylcystoine (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. Additionally, L2HGDH expression in RCC cells reduces histone methylation and suppresses
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