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Published in:

01-10-2015

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

Authors: Shuhei Noguchi, Masamitsu Eitoku, Shigeharu Moriya, Shinji Kondo, Hidenori Kiyosawa, Takashi Watanabe, Narufumi Suganuma

Published in: Lung | Issue 5/2015

Abstract

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)-β1. 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-β1 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-β1, and correlated with the localization of H3K27ac. However, genes up-regulated by TGF-β1 stimulation were not suppressed by VPA, with the exception of COL1A1.

Conclusions

Histone acetylation was down-regulated by TGF-β1 stimulation in A549 cells. VPA partially inhibited EMT and the decrease of histone acetylation, which plays an important role in the progression of EMT.

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Title: Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition
Authors: Shuhei Noguchi
Masamitsu Eitoku
Shigeharu Moriya
Shinji Kondo
Hidenori Kiyosawa
Takashi Watanabe
Narufumi Suganuma
Publication date: 01-10-2015
Publisher: Springer US
Published in: Lung / Issue 5/2015
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI: https://doi.org/10.1007/s00408-015-9776-9

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Abstract

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