Oncometabolite L-2-Hydroxyglutarate Promotes Oncogenesis of Renal Cell Carcinomas by Down-Regulating Differentiation

Abstract

L-2-Hydroxyglutarate (L2HG) overproducing Renal Cell Carcinomas (RCCs) arise in the kidney due to the genetic loss of L-2HG Dehydrogenase (L2HGDH), the enzyme responsible for the metabolism of L2HG. The overproduced 2-Hydroxyglutarate (2HG) promotes tumorigenesis by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation 5-methylcytosine (5mC) dioxygenase (TET) enzymes as well as histone demethylases. The resulting epigenetic changes alter the phenotype of renal proximal tubule (RPT) cells, the cells of origin of RCCs. This report describes the consequences of increased L2HG on the differentiation of RPT cells, one of the initial steps in promoting tumorigenesis. Presumably, similar alterations promote the expansion of renal cancer stem-cells and tumorigenesis.