HDAC6/FOXP3/HNF4α Axis Promotes Bile Acids Induced Gastric Intestinal Metaplasia

Abstract Background: Gastric intestinal metaplasia (IM) is an important precancerous lesion. Our previous study has shown that ectopic expression of HDAC6 promotes the activation of intestinal markers in bile acids (BA) induced gastric IM cells; however, the mechanism underlying how HDAC6-mediated epigenetic modifications regulate intestinal markers is not clear.Methods: RNA-sequencing (RNA-seq) was used to detect the molecular changes in GES-1 cells after HDAC6 overexpression. The potential binding sites of FOXP3 with the promoter region of HNF4α were verified by ChIP and luciferase reporter gene assays. The ChIP assay was also used to detect the histone deacetylation. The levels of mucin in gastric or intestinal mucosa were detected by AB-PAS staining. Transgenic mice were used to explore the pro-metaplastic function of DCA and HNF4α in vivo.Results: Deoxycholic acid (DCA) upregulated HDAC6 in gastric cells, which further inhibited the transcription of FOXP3. Then, FOXP3 transcriptionally inhibited HNF4α, which further inhibits the expression of downstream intestinal markers. These molecules have been shown to be clinically relevant, as FOXP3 levels were negatively correlated with HDAC6 and HNF4α in IM tissues. Transgenic mice experiments confirmed that HNF4α overexpression combined with DCA induced gastric mucosa to secrete intestinal mucus and caused an abnormal mucosal structure. Conclusions: Our findings suggest that HDAC6 reduces FOXP3 through epigenetic modification, thus forming HDAC6/FOXP3/HNF4α axis to promote gastric IM. Inhibition of HDAC6 may be a potential approach to prevent gastric IM in patients with bile reflux.