Histone deacetylase inhibitor m-carboxycinnamic acid bis-hydroxamide attenuates plasminogen activator inhibitor-1 expression in human pleural mesothelial cells

Chi Li Chung, Joen Rong Sheu, Wei Lin Chen, Yung Chen Chou, Che Jen Hsiao, Shih Hsin Hsiao, Ming Jen Hsu, Yu Wen Cheng, George Hsiao

研究成果: 雜誌貢獻文章

8 引文 斯高帕斯(Scopus)

摘要

Plasminogen activator inhibitor-1 (PAI-1), primarily up-regulated by transforming growth factor (TGF)-β, is essential in the development of fibrosis. Histone deacetylase (HDAC) was shown to modulate gene expression and fibrogenesis in various tissues. However, the implications of HDAC in terms of PAI-1 expression and pleural fibrosis remain unclear. In this study, we examined the effects of m-carboxycinnamic acid bis-hydroxamide (CBHA), a hybrid-polar HDAC inhibitor, on the TGF-β1-induced expression of PAI-1 in a human pleural mesothelial cell line (MeT-5A). MeT-5A cells were treated with TGF-β1 in the presence or absence of CBHA.We assayed the expression and stability of PAI-1 mRNA and protein, PAI-1 promoter activity, the activation of Smad signaling, the protein-protein interactions of Smads with transcriptional cofactors Sp1 and coactivator p300, and the expression of the mRNA-stabilizing protein nucleolin. The results indicate that CBHA significantly inhibited TGF-β1-induced PAI-1 mRNA and protein expression, and attenuated PAI-1 promoter activity in MeT-5A cells. CBHA abrogated TGF-β1-induced Smad4 nuclear translocation, but not Smad2/3 activation. Furthermore, the association of Smad4 with p300, but not with Sp1, was disrupted by CBHA. Alternatively, CBHA suppressed TGF-β1-induced nucleolin expression, and thereby destabilized PAI-1 mRNA and decreased PAI-1 protein concentrations. These findings suggest that the inhibition of HDAC activity by CBHA may attenuate PAI-1 expression through the modulation of cellular signaling at multiple levels. Given the down-regulating effect of CBHA on PAI-1 expression, HDAC inhibitors should be tested further in animal models as potential therapeutic agents for pleural fibrosis.
原文英語
頁(從 - 到)437-445
頁數9
期刊American Journal of Respiratory Cell and Molecular Biology
46
發行號4
DOIs
出版狀態已發佈 - 四月 2012

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

指紋 深入研究「Histone deacetylase inhibitor m-carboxycinnamic acid bis-hydroxamide attenuates plasminogen activator inhibitor-1 expression in human pleural mesothelial cells」主題。共同形成了獨特的指紋。

  • 引用此