RRC ID 38140
Author Noguchi S, Eitoku M, Moriya S, Kondo S, Kiyosawa H, Watanabe T, Suganuma N.
Title Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition.
Journal Lung
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.
Volume 193(5)
Pages 691-700
Published 2015-10
DOI 10.1007/s00408-015-9776-9
PII 10.1007/s00408-015-9776-9
PMID 26286207
MeSH Acetylation Antigens, CD Cadherins / genetics Cell Line, Tumor Cell Survival / drug effects Collagen Type I / genetics Epithelial-Mesenchymal Transition / genetics* Gene Expression Regulation / drug effects* Histone Code / drug effects Histone Deacetylase Inhibitors / pharmacology* Histones / metabolism Humans Inhibitor of Differentiation Protein 2 / genetics Lung Neoplasms / genetics* Oligonucleotide Array Sequence Analysis Phosphorylation / drug effects Plasminogen Activator Inhibitor 1 / genetics Proteins / genetics RNA / analysis Smad2 Protein / metabolism Transforming Growth Factor beta1 / pharmacology* Valproic Acid / pharmacology*
IF 2.231
Times Cited 11
Human and Animal Cells