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

doi:10.1073/pnas.1712625115

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

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35 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 language	English (US)
Pages (from-to)	1057-1062
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	5
DOIs	https://doi.org/10.1073/pnas.1712625115
State	Published - Jan 30 2018

Keywords

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

ASJC Scopus subject areas

General

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10.1073/pnas.1712625115

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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

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

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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.",

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AU - Cook, Beth

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AU - Theiss, Arianne L.

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PY - 2018/1/30

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N2 - 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.

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

Abstract

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