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
  • 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. [email protected].
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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