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 language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jan 30 2018|
Bibliographical noteFunding Information:
We thank Dr. Richard Bruick and Hanzhi Wang (University of Texas Southwestern Medical Center) for assistance with the hypoxic incubator, Arwa S. Kathiria and Dr. Teodoro Bottiglieri for technical assistance, and Dr. Stuart J. Spechler (Baylor Scott & White Research Institute) for thoughtful suggestions during the preparation of this manuscript.
- Colitis-associated cancer
- Dysplasia metabolites
- Inflammatory bowel disease