HDAC6/FOXP3/HNF4α axis promotes bile acids induced gastric intestinal metaplasia.
HDAC6/FOXP3/HNF4α axis promotes bile acids induced gastric intestinal metaplasia.
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DOI：
10.21203/rs.3.rs-155411/v1
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Na Wang;Siran Wu;Luyao Zhang;Min Chen;Jiaoxia Zeng;Guofang Lu;Fenli Zhou;Qiong Wu;Junye Liu;Yongquan Shi
中科院分区：
文献类型：
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作者：
Na Wang;Siran Wu;Luyao Zhang;Min Chen;Jiaoxia Zeng;Guofang Lu;Fenli Zhou;Qiong Wu;Junye Liu;Yongquan Shi
摘要胆汁反流是引起胃肠道上皮化生的主要原因之一，而肠上皮化生是胃肠道的重要癌前病变。我们以前的研究表明，异位表达组蛋白去乙酰化酶6（HDAC 6）促进激活胆汁酸（BA）诱导的胃IM细胞中的肠标志物;然而，HDAC 6介导的表观遗传修饰如何调节肠标志物的机制尚不清楚。本研究旨在探讨HDAC 6的下游靶点及其在BA诱导胃IM过程中的作用机制。我们证明，脱氧胆酸（DCA）上调HDAC 6在胃细胞中，这进一步抑制叉头盒蛋白3（FOXP 3）的转录。然后，FOXP 3转录抑制肝细胞核因子4α（HNF 4 α），这进一步抑制下游肠道标志物的表达。这些分子已被证明具有临床相关性，因为IM组织中FOXP 3水平与HDAC 6和HNF 4 α呈负相关。转基因小鼠实验证实HNF 4 α过表达联合DCA处理可诱导胃粘膜分泌肠粘液，引起粘膜结构异常。我们的研究结果表明，HDAC 6通过表观遗传修饰减少FOXP 3，从而形成闭环HDAC 6/FOXP 3/HNF 4 α，以促进胃IM。抑制HDAC 6可能是预防胆汁反流患者胃IM的潜在方法。
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.