title: L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Shim
authors.affiliation: Department of Molecular Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jubilee
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Daniel
authors.initials: D
authors.lastname: Benson
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Vishwas
authors.initials: V
authors.lastname: Parekh
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kho
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Arindam P
authors.initials: AP
authors.lastname: Ghosh
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Richard
authors.initials: R
authors.lastname: Kirkman
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sadanan
authors.initials: S
authors.lastname: Velu
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Balachandra
authors.initials: B
authors.lastname: Chenna
authors.affiliation: Department of Physiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Shane L
authors.initials: SL
authors.lastname: Rea
authors.affiliation: Department of Physiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mishur
authors.affiliation: Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Johnson-Pais
authors.affiliation: Metabolon, Durham, North Carolina.
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas. Audie L. Murphy Veterans Hospital, San Antonio, Texas.
authors.forename: Karen
authors.initials: K
authors.lastname: Block
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama. sudarshan@uab.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sudarshan
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005977:Glutarates / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D005977:Glutarates; D012333:RNA, Messenger; C019417:alpha-hydroxyglutarate