2. Academic Validation
  3. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer

  • Cancer Discov. 2014 Nov;4(11):1290-8. doi: 10.1158/2159-8290.CD-13-0696.
Eun-Hee Shim 1,  Carolina B Livi 2,  Dinesh Rakheja 3,  Jubilee Tan 1,  Daniel Benson 1,  Vishwas Parekh 4,  Eun-Young Kho 1,  Arindam P Ghosh 1,  Richard Kirkman 1,  Sadanan Velu 5,  Shilpa Dutta 5,  Balachandra Chenna 5,  Shane L Rea 6,  Robert J Mishur 6,  Qiuhua Li 7,  Teresa L Johnson-Pais 7,  Lining Guo 8,  Sejong Bae 9,  Shi Wei 4,  Karen Block 10,  Sunil Sudarshan 11
Affiliations

Affiliations

  • 1 Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 2 Department of Molecular Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
  • 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 4 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 5 Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama.
  • 6 Department of Physiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
  • 7 Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
  • 8 Metabolon, Durham, North Carolina.
  • 9 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
  • 10 Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas. Audie L. Murphy Veterans Hospital, San Antonio, Texas.
  • 11 Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama. sudarshan@uab.edu.
PMID: 25182153 DOI: 10.1158/2159-8290.CD-13-0696
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.

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