4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation
4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation
复制标题
4-苯基丁酸通过组蛋白脱乙酰酶抑制介导的IL-8上调促进胃癌细胞迁移
DOI：
10.1080/15592294.2019.1700032
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发表时间：
2019-12-09
期刊：
影响因子：
3.7
通讯作者：
Che, Xiaofang
中科院分区：
文献类型：
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作者：
Shi, Xiaonan;Gong, Libao;Che, Xiaofang
组蛋白乙酰化受组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）的调控。它与基因转录和表达有关。4-苯丁酸（4-PBA）是一种HDAC抑制剂（HDACi），可以通过增加组蛋白乙酰化水平来抑制癌细胞增殖。然而，4-PBA在临床试验中没有显示出任何疗效。本研究中，我们发现4-PBA可诱导E-cadherin异位表达的胃癌细胞系MGC-803和BGC-823发生上皮-间质转化（EMT）。基于表达谱芯片，IL-8是4-PBA最显著上调的基因，并被选择用于进一步研究。IL-8的敲低通过阻断下游Gab 2-ERK通路的激活而部分阻止4-PBA诱导的EMT。CHIP实验进一步证实乙酰-H3直接与IL-8的启动子区结合，促进IL-8的转录。因此，本研究的结果表明，4-PBA介导的HDAC活性抑制可以通过乙酰组蛋白介导的IL-8上调和下游Gab 2/ERK激活诱导胃癌细胞中的EMT。这些数据表明了4-PBA在临床试验中失败的可能原因。
ABSTRACT Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is associated with gene transcription and expression. 4-Phenylbutyric acid (4-PBA), an HDAC inhibitor (HDACi), can inhibit cancer cell proliferation by increasing the level of histone acetylation. However, 4-PBA did not show any efficacy in clinical trials. In this study, we found that 4-PBA induced epithelial–mesenchymal transition (EMT) in gastric cancer cell lines MGC-803 and BGC-823 with ectopic E-cadherin expression. Based on the expression profile microarray, IL-8 was the most significantly up-regulated gene by 4-PBA, and was selected for further investigation. Knockdown of IL-8 partially prevented 4-PBA-induced-EMT by blocking the activation of the downstream Gab2-ERK pathway. Furthermore, CHIP assay confirmed that acetyl-H3 directly combined with the promoter region of IL-8 to promote its transcription. Therefore, the results of this study demonstrated that 4-PBA-mediated inhibition of HDAC activity could induce EMT in gastric cancer cells via acetyl-histone-mediated IL-8 upregulation, and the downstream Gab2/ERK activation. These data indicated the possible reason for the failure of 4-PBA in clinical trials.