Inhibition of Histone Deacetylation by MS-275 Alleviates Colitis by Activating the Vitamin D Receptor

Abstract

Background Ulcerative colitis [UC] is a common chronic inflammatory bowel disease without curative treatment. Methods We conducted gene set enrichment analysis to explore potential therapeutic agents for UC. Human colon tissue samples were collected to test H3 acetylation in UC. Both in vivo and in vitro colitis models were constructed to verify the role and mechanism of H3 acetylation modification in UC. Intestine-specific vitamin D receptor [VDR]-/- mice and VD [vitamin D]-deficient diet-fed mice were used to explore downstream molecular mechanisms accordingly. Results According to the Connectivity Map database, MS-275 [class I histone deacetylase inhibitor] was the top-ranked agent, indicating the potential importance of histone acetylation in the pathogenesis of UC. We then found that histone H3 acetylation was significantly lower in the colon epithelium of UC patients and negatively associated with disease severity. MS-275 treatment inhibited histone H3 deacetylation, subsequently attenuating nuclear factor kappa B [NF-κB]-induced inflammation, reducing cellular apoptosis, maintaining epithelial barrier function, and thereby reducing colitis activity in a mouse model of colitis. We also identified VDR as be a downstream effector of MS-275. The curative effect of MS-275 on colitis was abolished in VDR-/- mice and in VD-deficient diet-fed mice and VDR directly targeted p65. In UC patients, histone H3 acetylation, VDR and zonulin-1 expression showed similar downregulation patterns and were negatively associated with disease severity. Conclusions We demonstrate that MS-275 inhibits histone deacetylation and alleviates colitis by ameliorating inflammation, reducing apoptosis, and maintaining intestinal epithelial barrier via VDR, providing new strategies for UC treatment.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis

“…As reported, gut epithelial VDR inhibited colitis by protecting the mucosal epithelial barrier and maintaining mucosal integrity (19,27), although only a few studies illustrated the mechanism of this protective effect against colitis. Here, we found that VDR knockout in the intestinal epithelium suppressed mucosal absorptive function in vivo (Fig.…”

“…In addition, VDR had an inhibitory effect on the phosphorylation of Smad2/3, which is a classic downstream molecule of TGFβ1. To verify the effects of VDR on intestinal epithelia in EMT-related fibrosis, we established intestinal fibrosis models with intestinal epithelial-specific VDR-knockout mice (20) and littermate controls. Mice with epithelial VDR deficiency developed worsened intestinal fibrosis in both the chronic TNBS and DSS models, followed by exacerbated EMT and mitochondrial dysfunction.…”

“…The vitamin D-sufficient/deficient diet and the corresponding control diet were purchased from Shuyishuer Bio (Changzhou, China). Our previous study described the intestine-specific VDR-knockout mice (27), and the experimental mice were bred from VDR flox/flox mice crossed with intestine-specific Villin-Cre mice, while the controls were sibling littermates. All mouse experiments were approved by the Animal Care and Use Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University.…”

“…VDR forms a vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex and then binds to specific DNA sequences after being activated by 1,25(OH) 2 D 3 (17). The inhibitory effects of vitamin D (VD) and VDR on acute colitis have been previously reported (18)(19)(20), but the potential effect of VDR on intestinal fibrosis is currently poorly understood. Previous studies reported diminished VDR protein levels in the intestines of CD patients compared with control tissues (21).…”

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

“…Lysine acetylation is a common posttranslational modification (PTM) regulating protein stability, subcellular localization, and function [17]. Acetylation of histone and nonhistone was reported to be involved in many diseases, including aging-associated chronic inflammation and insulin resistance [18], cancer [19][20][21], colitis [22], and Alzheimer's disease [23]. In previous work, we analyzed the lysine acetylproteome in three primary cervical cancer tissues and corresponding adjacent normal tissues by using the label-free proteomics approach and found that acetylation levels of CLIC1 at lysine 131 were significantly increased in tumor tissues.…”