Histone Deacetylase Inhibitor m-Carboxycinnamic Acid bis-Hydroxamide Attenuates Plasminogen Activator Inhibitor–1 Expression in Human Pleural Mesothelial Cells
| Autor: | George Hsiao, Che Jen Hsiao, Joen Rong Sheu, Yung Chen Chou, Ming Jen Hsu, Shih Hsin Hsiao, Chi Li Chung, Yu Wen Cheng, Wei Lin Chen |
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| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
Sp1 Transcription Factor medicine.drug_class Clinical Biochemistry Active Transport Cell Nucleus Smad2 Protein SMAD Histones Transforming Growth Factor beta1 chemistry.chemical_compound Plasminogen Activator Inhibitor 1 Coactivator medicine Humans Heterogeneous Nuclear Ribonucleoprotein D0 p300-CBP Transcription Factors Smad3 Protein Heterogeneous-Nuclear Ribonucleoprotein D RNA Processing Post-Transcriptional Promoter Regions Genetic Molecular Biology Cells Cultured Smad4 Protein Histone deacetylase 5 HDAC11 Chemistry Histone deacetylase inhibitor RNA-Binding Proteins Epithelial Cells Cell Biology Phosphoproteins Histone Deacetylase Inhibitors Gene Expression Regulation Cinnamates Plasminogen activator inhibitor-1 Cancer research Pleura Histone deacetylase Plasminogen activator Signal Transduction |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 46:437-445 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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