Histone deacetylase inhibitor m-carboxycinnamic acid bis-hydroxamide attenuates plasminogen activator inhibitor-1 expression in human pleural mesothelial cells.
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.
Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taiwan.
Chi-Li
CL
Chung
Joen-Rong
JR
Sheu
Wei-Lin
WL
Chen
Yung-Chen
YC
Chou
Che-Jen
CJ
Hsiao
Shih-Hsin
SH
Hsiao
Ming-Jen
MJ
Hsu
Yu-Wen
YW
Cheng
George
G
Hsiao
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D010994:Pleura / Q000166:cytology / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097796:Nucleolin
D002934:Cinnamates; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D016601:RNA-Binding Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; D050880:p300-CBP Transcription Factors; D000097796:Nucleolin; C000630986:HNRNPD protein, human; C051321:SERPINE1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C111238:carboxycinnamic acid bishydroxamide