4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation

被引：14

作者：

Shi, Xiaonan ^{[1
,2
,3
]}

Gong, Libao ^{[1
,2
]}

Liu, Yunpeng ^{[1
,2
]}

Hou, Kezuo ^{[1
,2
]}

Fan, Yibo ^{[1
,2
]}

Li, Ce ^{[1
,2
]}

Wen, Ti ^{[1
,2
]}

Qu, Xiujuan ^{[1
,2
]}

Che, Xiaofang ^{[1
,2
]}

机构：

[1] First Hosp China Med Univ, Dept Med Oncol, Shenyang, Peoples R China

[2] First Hosp China Med Univ, Key Lab Anticanc Drugs & Biotherapy Liaoning Prov, Shenyang, Peoples R China

[3] Zhengzhou Univ, Affiliated Hosp 1, Dept Oncol, Zhengzhou, Henan, Peoples R China

来源：

EPIGENETICS | 2020年 / 15卷 / 6-7期

基金：

中国国家自然科学基金;

关键词：

4-PBA; histone deacetylase inhibitor; histone acetylation; IL-8; EMT; gastric cancer cell; INTERLEUKIN-8; EXPRESSION; MESENCHYMAL TRANSITION; SODIUM PHENYLBUTYRATE; PATHWAY; INDEPENDENCE; COMBINATION; PROGRESSION; INDUCTION; PROGNOSIS; CARCINOMA;

D O I：

10.1080/15592294.2019.1700032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：632 / 645

页数：14

共 38 条

[1] Potentiation of tumor necrosis factor-induced NF-κB activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of IκBα [J].