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Colonic inflammation and cancer are driven by elevated D‐2‐hydroxyglutarate levels in an EglN1‐dependent mechanism
Author(s) -
Theiss Arianne L.,
Han Jie,
Turner Kevin O.,
Genta Robert M.,
Sweetman Lawrence
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1046.1
Subject(s) - colitis , carcinogenesis , cancer , inflammation , cancer research , ulcerative colitis , colorectal cancer , medicine , immunology , disease
Emerging evidence suggests a crucial role for altered expression of enzymes with functions in cellular metabolism in the pathogenesis of inflammation and cancer. But the detailed molecular mechanisms that link these alterations to carcinogenesis remain elusive. Here, we identify a novel role for altered metabolism of D‐2‐hydroxyglutarate (D2HG) in colitis and colitis‐associated colon cancer. We found that the levels of D2HG were elevated in the urine of mice during dextran sodium sulfate (DSS)‐induced colitis. In a mouse model of colitis‐associated cancer, intraperitoneal injection of D2HG resulted in delayed recovery from colitis and severe tumorigenesis. The colonic expression of D‐2‐hydroxyglutarate dehydrogenase (D2HGDH), an enzyme that eliminates D2HG, was decreased during DSS colitis and human ulcerative colitis (UC) but unaltered in mouse or UC tumors. Mechanistically, we demonstrate that elevated expression of Egg‐laying defective Nine 1 (EglN1) inhibited hypoxia inducible factor (Hif)‐1a, which in turn attenuated D2HGDH transcription, thereby resulting in elevated D2HG. Furthermore, pharmacological inhibition of EglN1 ameliorated colitis‐associated cancer in mice. Thus, we have identified a novel regulatory mechanism where D2HG promotes colonic inflammation and carcinogenesis, which may provide functional therapeutic targets to inhibit the progression from colitis to cancer. Support or Funding Information Cancer Prevention & Research Institute of Texas grant RP150638 (A.L.T) and Charles A. Sammons Cancer Center, Baylor University Medical Center grant (A.L.T).