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

Jie Han, Dakota Jackson, Janette Holm, Kevin Turner, Paula Ashcraft, Xuan Wang, Beth Cook, Erland Arning, Robert M. Genta, K. Venuprasad, Rhonda F. Souza, Lawrence Sweetman, Arianne L. Theiss

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

D-2-hydroxyglutarate (D2HG) is produced in the tricarboxylic acid cycle and is quickly converted to α-ketoglutarate by D-2-hydroxy-glutarate 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.

Original languageEnglish (US)
Pages (from-to)1057-1062
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
StatePublished - Jan 30 2018

Keywords

  • Colitis-associated cancer
  • Dysplasia metabolites
  • Hif-1α
  • Inflammatory bowel disease

ASJC Scopus subject areas

  • General

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    Han, J., Jackson, D., Holm, J., Turner, K., Ashcraft, P., Wang, X., Cook, B., Arning, E., Genta, R. M., Venuprasad, K., Souza, R. F., Sweetman, L., & Theiss, A. L. (2018). Elevated D-2-hydroxyglutarate during colitis drives progression to colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 115(5), 1057-1062. https://doi.org/10.1073/pnas.1712625115