4‐Phenybutyric acid promotes gastric cancer cell migration via histone deacetylase inhibition‐mediated HER3/HER4 up‐regulation
4‐Phenybutyric acid promotes gastric cancer cell migration via histone deacetylase inhibition‐mediated HER3/HER4 up‐regulation
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DOI：
10.1002/cbin.10866
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发表时间：
2018-01
影响因子：
3.9
通讯作者：
Xiaonan Shi;Chunlei Zheng;Ce Li;K. Hou;Xiaoxun Wang;Zichang Yang;Chang Liu;Yunpeng Liu;X. Che;X. Qu
中科院分区：
文献类型：
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作者：
Xiaonan Shi;Chunlei Zheng;Ce Li;K. Hou;Xiaoxun Wang;Zichang Yang;Chang Liu;Yunpeng Liu;X. Che;X. Qu
组蛋白乙酰化失调在肿瘤发生发展中起重要作用。组蛋白乙酰化调节基因的转录和表达，并受组蛋白乙酰转移酶（Histone acetyltransferase， HAT）和组蛋白去乙酰化酶（Histone deacetylase， HDAC）的可逆调控。作为HDAC抑制剂，4‐苯基丁酸（4‐PBA）可以通过抑制HDAC活性来增加组蛋白乙酰化水平。虽然4 - PBA在体外抑制肿瘤细胞的增殖，但临床试验未能显示4 - PBA对难治性实体瘤的益处。在这里，我们发现4 - PBA可以增强胃癌细胞的迁移能力。研究表明，HER3/HER4的上调和HER3/HER4‐ERK通路的激活参与了4‐PBA诱导的胃癌细胞迁移。HER3/HER4的敲低阻断了HER3/HER4‐ERK的激活，部分阻止了4‐PBA诱导的细胞迁移。与此一致的是，ERK抑制剂PD98059也部分阻止了4 - PBA诱导的细胞迁移。此外，在4‐PBA‐处理后，检测到乙酰化组蛋白水平增强，并且通过ChIP证实HER3和HER4启动子区域的组蛋白3乙酰化。这些结果表明，4 - PBA通过上调HER3/HER4促进胃癌细胞迁移，随后乙酰组蛋白水平升高和ERK信号的激活。这些新发现为4 - PBA在癌症治疗中的应用提供了重要的考虑因素。
Dysregulation of histone acetylation plays an important role in tumor development. Histone acetylation regulates gene transcription and expression, which is reversibly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). As an HDAC inhibitor, 4‐phenylbutyric acid (4‐PBA) can increase histone acetylation levels by inhibiting HDAC activity. While 4‐PBA inhibits proliferation of tumor cells in vitro, clinical trials have failed to show benefits of 4‐PBA for refractory solid tumors. Here, we found that 4‐PBA could enhance the migration capacity of gastric cancer cells. Upregulation of HER3/HER4 and activation of HER3/HER4‐ERK pathway was shown to be involved in 4‐PBA‐induced gastric cancer cell migration. Knockdown of HER3/HER4 blocked HER3/HER4‐ERK activation and partially prevented 4‐PBA‐induced cell migration. Consistently, the ERK inhibitor PD98059 also partially prevented 4‐PBA‐induced cell migration. Moreover, enhanced levels of acetyl‐histones were detected following 4‐PBA‐treatment, and histone3 acetylation in promoter regions of HER3 and HER4 were confirmed by ChIP. These results demonstrate that 4‐PBA promotes gastric cancer cells migration through upregulation of HER3/HER4 subsequent to increased levels of acetyl‐histone and activation of ERK signaling. These novel findings provide important considerations for the use of 4‐PBA in cancer therapeutics.