Abstract
Intestinal fibrosis is one of the common pathophysiological processes in inflammatory bowel diseases (IBDs). Previously it has been demonstrated that epithelial-mesenchymal transition (EMT) can contribute to the development of intestinal fibrosis. Here we report that conditional ablation of SIRT1, a class III lysine deacetylase, in intestinal epithelial cells exacerbated 2, 4, 6-trinitro-benzene sulfonic acid (TNBS) induced intestinal fibrosis in mice. SIRT1 activity, but not SIRT1 expression, was down-regulated during EMT likely due to up-regulation of its inhibitor deleted in breast cancer 1 (DBC1). TGF-β augmented the recruitment of KDM4A, a histone H3K9 demethylase, to the DBC1 promoter in cultured intestinal epithelial cells (IEC-6) leading to DBC1 trans-activation. KDM4A depletion or inhibition abrogated DBC1 induction by TGF-β and normalized SIRT1 activity. In addition, KDM4A deficiency attenuated TGF-β induced EMT in IEC-6 cells. In conclusion, our data identify a KDM4-DBC1-SIRT1 pathway that regulates EMT to contribute to intestinal fibrosis.
Highlights
Inflammatory bowl diseases (IBDs) refer to a group of relapsing and heterogeneous intestinal disorders exemplified by Crohn’s disease and ulcerative colitis (Ananthakrishnan, 2015)
Picrosirius red staining confirmed that deposition of collagenous tissues in the small intestines and the colons was up-regulated in the mice following trinitro-benzene sulfonic acid (TNBS) injection whereas the CKO mice exhibited more prominent intestinal fibrosis than the wild type (WT) mice (Figure 1C)
We provide evidence that supports the involvement of a KDM4A-deleted in breast cancer 1 (DBC1)-Silent information regulator 1 (SIRT1) axis in the regulation of epithelial-mesenchymal transition (EMT) potentially contributing to intestinal fibrosis
Summary
Inflammatory bowl diseases (IBDs) refer to a group of relapsing and heterogeneous intestinal disorders exemplified by Crohn’s disease and ulcerative colitis (Ananthakrishnan, 2015). Patients diagnosed with IBDs typically present chronic abdominal pain, fever, abscess, and fistula; these patients, in most severe cases and in the long term, Epigenetic Regulation of EMT can develop intestinal cancer (D’Haens, 2010). IBDs are influenced by the genetics and the environment. Over 160 loci have been identified to confer altered susceptibility to the development of IBDs in humans (Jostins et al, 2012). On the other hand, smoking, diets, life style, pollution, and even personal hygiene have been reported as potential environmental risk factors for IBDs (Leong, 2010). IBDs are clinically considered as a gastroenterological disorder, extraintestinal systems, the immune system in particular, play pivotal roles (Digby-Bell et al, 2020)
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