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

被引：6
作者：
Chen, Baoyu [1 ]
Dong, Wenhui [1 ]
Shao, Tinghui [1 ]
Miao, Xiulian [2 ,3 ]
Guo, Yan [2 ,3 ]
Liu, Xingyu [2 ,3 ]
Feng, Yifei [4 ,5 ]
机构：
[1] Nanjing Med Univ, Dept Pathophysiol, Nanjing, Peoples R China
[2] Liaocheng Univ, Coll Life Sci, Liaocheng, Shandong, Peoples R China
[3] Liaocheng Univ, Inst Biomed Res, Liaocheng, Shandong, Peoples R China
[4] Nanjing Med Univ, Dept Gen Surg, Affiliated Hosp 1, Nanjing, Peoples R China
[5] Nanjing Med Univ, Sch Clin Med 1, Nanjing, Peoples R China
来源：
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2021年 / 9卷
关键词：
intestinal fibrosis; epithelial-mesenchymal transition; SIRT1; transcriptional regulation; epigenetics; histone demethylase; POTENTIAL THERAPEUTIC TARGET; CANCER METASTASIS; SIRT1; SUPPRESSES; RISK-FACTORS; FIBROSIS; ACTIVATION; COLITIS; IBD; MECHANISMS; ALPHA;
D O I：
10.3389/fcell.2021.697614
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
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-beta 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-beta and normalized SIRT1 activity. In addition, KDM4A deficiency attenuated TGF-beta 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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页数：13
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