A KDM4-DBC1-SIRT1 Axis Contributes to TGF-b Induced Mesenchymal Transition of Intestinal Epithelial Cells

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Oct 11

PMID 34631698

Citations 4

Authors

Baoyu Chen

Wenhui Dong

Tinghui Shao

Xiulian Miao

Yan Guo

Xingyu Liu

Yifei Feng

Affiliations

Soon will be listed here.

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 -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.

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