Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer

Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1057-1062. doi: 10.1073/pnas.1712625115. Epub 2018 Jan 16.

Abstract

d-2-hydroxyglutarate (D2HG) is produced in the tricarboxylic acid cycle and is quickly converted to α-ketoglutarate by d-2-hydroxyglutarate dehydrogenase (D2HGDH). In a mouse model of colitis-associated colon cancer (CAC), urine level of D2HG during colitis correlates positively with subsequent polyp counts and severity of dysplasia. The i.p. injection of D2HG results in delayed recovery from colitis and severe tumorigenesis. The colonic expression of D2HGDH is decreased in ulcerative colitis (UC) patients at baseline who progress to cancer. Hypoxia-inducible factor (Hif)-1α is a key regulator of D2HGDH transcription. Our study identifies urine D2HG and tissue D2HGDH expression as biomarkers to identify patients at risk for progressing from colitis to cancer. The D2HG/D2HGDH pathway provides potential therapeutic targets for the treatment of CAC.

Keywords: Hif-1α; colitis-associated cancer; dysplasia; inflammatory bowel disease; metabolites.

MeSH terms

  • Animals
  • Apoptosis
  • Azoxymethane / chemistry
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • Caco-2 Cells
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Colitis / metabolism*
  • Colitis / pathology*
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / pathology
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Dextran Sulfate / chemistry
  • Disease Progression
  • Glutarates / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation
  • Intestinal Mucosa / pathology
  • Mice
  • Risk

Substances

  • Biomarkers, Tumor
  • Glutarates
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • alpha-hydroxyglutarate
  • Dextran Sulfate
  • Azoxymethane

Associated data

  • GENBANK/KX227379