Putative Oncometabolite in Renal Cancer

Through unbiased metabolomics, we identifi ed 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, specifi cally 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 identifi es l -2HG as an epigenetic modifi er 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 fi ndings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer. Cancer Discov; 4(11); 1290–8. ©2014 AACR. l -2-Hydroxyglutarate: An Epigenetic Modifi er and Putative Oncometabolite in Renal Cancer 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 10,11 , and Sunil Sudarshan 1 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. 11 Audie L. Murphy Veterans Hospital, San Antonio, Texas . Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Sunil Sudarshan, University of Alabama at Birmingham, 1105 Faculty Offi ce Tower, 510 20th Street South, Birmingham, AL 35294. Phone: 205-996-8765; Fax: 205-934-4933; E-mail: sudarshan@ uab.edu doi: 10.1158/2159-8290.CD-13-0696 ©2014 American Association for Cancer Research. INTRODUCTION One of the clearest examples of the role of metabolism in cancer is the recent identifi cation of oncometabolites, small molecules with putative oncogenic properties. Mutations of fumarate hydratase ( FH ), succinate dehydrogenase ( SDH ), and isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) in tumors lead to elevated levels of fumarate, succinate, and 2-hydroxyglutarate (2HG), respectively ( 1, 2 ). In cells with FH and SDH mutations, precursor metabolites (fumarate and succinate) accumulate on July 3, 2017. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst September 2, 2014; DOI: 10.1158/2159-8290.CD-13-0696