Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition

被引：27

作者：

Noguchi, Shuhei ^{[1
]}

Eitoku, Masamitsu ^{[1
]}

Moriya, Shigeharu ^{[2
]}

Kondo, Shinji ^{[3
]}

Kiyosawa, Hidenori ^{[1
]}

Watanabe, Takashi ^{[4
,5
]}

Suganuma, Narufumi ^{[1
]}

机构：

[1] Kochi Univ, Kochi Med Sch, Dept Environm Med, Nankoku, Kochi 7838505, Japan

[2] RIKEN, Ctr Sustainable Resource Sci, Biomass Engn Program Cooperat Div, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan

[3] Natl Inst Polar Res, Res Integrat Ctr, Res Org Informat & Syst, Tachikawa, Tokyo 1908518, Japan

[4] Kochi Univ Technol, Org Reg Alliances, Kochi 7828502, Japan

[5] Kumamoto Univ, Grad Sch Pharmaceut Sci, Sch Pharm, Chuo Ku, Kumamoto 8620973, Japan

来源：

LUNG | 2015年 / 193卷 / 05期

关键词：

Pulmonary fibrosis; Non-small cell lung cancer; Histone modification; Epithelial-to-mesenchymal transition; Sodium valproate; RNA-Seq; LUNG-CANCER CELLS; PULMONARY-FIBROSIS; HISTONE MODIFICATIONS; A549; INHIBITION; TGF-BETA-1; DIFFERENTIATION; FIBROBLASTS; MIGRATION; EMT;

D O I：

10.1007/s00408-015-9776-9

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Purpose Epithelial-to-mesenchymal transition (EMT) is an important mechanism in cancer metastasis and pulmonary fibrosis. Previous studies demonstrated effect of histone H3 and H4 acetylation in cancer and pulmonary fibrosis, so we hypothesized that histone modification might play a crucial role in gene regulation during EMT. In this study, we investigated the mechanism behind EMT by analyzing comprehensive gene expression and the effect of sodium valproate (VPA), a class I histone deacetylase inhibitory drug, on histone modification. Methods EMT was induced in human alveolar epithelial cells (A549) using 5 ng/mL of transforming growth factor (TGF)-beta 1. Various concentrations of VPA were then administered, and Western blotting was used to analyze histone acetylation or methylation. Comprehensive gene expression analysis was carried out by RNA sequencing, and chromatin immunoprecipitation was performed with an anti-acetyl histone H3 lysine 27 antibody. Results TGF-beta 1 stimulation led to a decrease in histone acetylation, especially that of histone H3K27, and H3K27ac localization was decreased at particular gene loci. This decrease was recovered by VPA treatment, which also up-regulated the mRNA expression of genes down-regulated by TGF-beta 1, and correlated with the localization of H3K27ac. However, genes up-regulated by TGF-beta 1 stimulation were not suppressed by VPA, with the exception of COL1A1. Conclusions Histone acetylation was down-regulated by TGF-beta 1 stimulation in A549 cells. VPA partially inhibited EMT and the decrease of histone acetylation, which plays an important role in the progression of EMT.

引用

页码：691 / 700

页数：10

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