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

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.

Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression

“…It has been reported that DBC1 cooperates with SIRT1 to mediate different physiological functions within mammalian cells. For example, stimulation of DBC1 transcription inhibits SIRT1 activity, contributing to TGF-β-induced epithelial–mesenchymal transition ( Chen et al, 2021 ). Additionally, SIRT7 represses DBC1 transcription to promote thyroid tumorigenesis by binding to the promoter of DBC1 ( Li et al, 2019 ).…”

Zinc finger transcription factor Egf1 promotes non-alcoholic fatty liver disease

“…Whole-cell lysates were obtained by resuspending cell pellets in radioimmunoprecipitation assay (RIPA) buffer (50 mM Tris pH7.4, 150 mM NaCl, 1% Triton X-100) with freshly added protease inhibitor (Roche, Basel, Switzerland) as previously described. 29 Typically, 100 μl RIPA buffer was used for 1 × 10 6 cells. Moreover, 30 μg of protein was loaded in each lane and separated by 8% SDS-PAGE gel with all-blue protein markers (Bio-Rad, Hercules, CA, USA).…”

HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes

“…Transient transfections were performed with Lipofectamine LTX (for DNA plasmid) or Lipofectamine RNAiMax (For siRNA) per vendor recommendation. Luciferase activities were assayed 24-48 hours after transfection using a luciferase reporter assay system (Promega) as previously described [ 56 – 58 ].…”