Zhang Luyao, Wang Na, Chen Min, Wu Siran, Zeng Jiaoxia, Zhou Fenli, Wu Qiong, Liu Junye, Shi Yongquan
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University Xi'an, Shaanxi, China.
Department of Radiation Protective Medicine, Fourth Military Medical University Xi'an, Shaanxi, China.
Am J Cancer Res. 2022 Mar 15;12(3):1409-1422. eCollection 2022.
Bile reflux is one of the main causes of gastric intestinal metaplasia (IM) which is an important precancerous lesion. Our previous study has shown that ectopic expression of Histone deacetylase 6 (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. In this study, we aimed to investigate the downstream targets of HDAC6 and the underlying mechanism in the process of BA induced gastric IM. We demonstrated that deoxycholic acid (DCA) upregulated HDAC6 in gastric cells, which further inhibited the transcription of Forkhead box protein 3 (FOXP3). Then, FOXP3 transcriptionally inhibited Hepatocyte nuclear factor 4α (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 treatment induced gastric mucosa to secrete intestinal mucus and caused an abnormal mucosal structure. Our findings suggest that HDAC6 reduces FOXP3 through epigenetic modification, thus forming a closed loop HDAC6/FOXP3/HNF4α to promote gastric IM. Inhibition of HDAC6 may be a potential approach to prevent gastric IM in patients with bile reflux.
胆汁反流是胃肠化生（IM）的主要原因之一，胃肠化生是一种重要的癌前病变。我们之前的研究表明，组蛋白去乙酰化酶6（HDAC6）的异位表达促进了胆汁酸（BA）诱导的胃IM细胞中肠道标志物的激活；然而，HDAC6介导的表观遗传修饰如何调节肠道标志物的潜在机制尚不清楚。在本研究中，我们旨在研究HDAC6的下游靶点以及BA诱导胃IM过程中的潜在机制。我们证明，脱氧胆酸（DCA）上调胃细胞中的HDAC6，进而抑制叉头框蛋白3（FOXP3）的转录。然后，FOXP3转录抑制肝细胞核因子4α（HNF4α），进一步抑制下游肠道标志物的表达。这些分子已被证明与临床相关，因为在IM组织中FOXP3水平与HDAC6和HNF4α呈负相关。转基因小鼠实验证实，HNF4α过表达联合DCA处理可诱导胃黏膜分泌肠黏液并导致黏膜结构异常。我们的研究结果表明，HDAC6通过表观遗传修饰降低FOXP3，从而形成一个闭环HDAC6/FOXP3/HNF4α以促进胃IM。抑制HDAC6可能是预防胆汁反流患者胃IM的一种潜在方法。
