Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.
Publication/Presentation Date
1-30-2018
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.
Volume
115
Issue
5
First Page
1057
Last Page
1062
ISSN
1091-6490
Published In/Presented At
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
Disciplines
Medicine and Health Sciences
PubMedID
29339485
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article