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

7 Citations (Scopus)

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

Fingerprint

Glutarates
Colitis
Colorectal Neoplasms
Oxidoreductases
Urine
Hypoxia-Inducible Factor 1
Neoplasms
Citric Acid Cycle
Polyps
Ulcerative Colitis
Colonic Neoplasms
Carcinogenesis
Biomarkers
alpha-hydroxyglutarate
Injections
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Elevated D-2-hydroxyglutarate during colitis drives progression to colorectal cancer. / Han, Jie; Jackson, Dakota; Holm, Janette; Turner, Kevin; Ashcraft, Paula; Wang, Xuan; Cook, Beth; Arning, Erland; Genta, Robert M.; Venuprasad, K.; Souza, Rhonda F.; Sweetman, Lawrence; Theiss, Arianne L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 5, 30.01.2018, p. 1057-1062.

Research output: Contribution to journalArticle

Han, J, Jackson, D, Holm, J, Turner, K, Ashcraft, P, Wang, X, Cook, B, Arning, E, Genta, RM, Venuprasad, K, Souza, RF, Sweetman, L & Theiss, AL 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, vol. 115, no. 5, pp. 1057-1062. https://doi.org/10.1073/pnas.1712625115
Han, Jie ; Jackson, Dakota ; Holm, Janette ; Turner, Kevin ; Ashcraft, Paula ; Wang, Xuan ; Cook, Beth ; Arning, Erland ; Genta, Robert M. ; Venuprasad, K. ; Souza, Rhonda F. ; Sweetman, Lawrence ; Theiss, Arianne L. / Elevated D-2-hydroxyglutarate during colitis drives progression to colorectal cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 5. pp. 1057-1062.
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