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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-\u03b21\u2013induced expression of PAI-1 in a human pleural mesothelial cell line (MeT-5A). MeT-5A cells were treated with TGF-\u03b21 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\u2013protein 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-\u03b21\u2013induced PAI-1 mRNA and protein expression, and attenuated PAI-1 promoter activity in MeT-5A cells. CBHA abrogated TGF-\u03b21\u2013induced 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-\u03b21\u2013induced 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.<\/jats:p>","DOI":"10.1165\/rcmb.2011-0118oc","type":"journal-article","created":{"date-parts":[[2011,10,27]],"date-time":"2011-10-27T23:01:42Z","timestamp":1319756502000},"page":"437-445","source":"Crossref","is-referenced-by-count":10,"title":["Histone Deacetylase Inhibitor\n                    <i>m<\/i>\n                    -Carboxycinnamic Acid bis-Hydroxamide Attenuates Plasminogen Activator Inhibitor\u20131 Expression in Human Pleural Mesothelial Cells"],"prefix":"10.1093","volume":"46","author":[{"given":"Chi-Li","family":"Chung","sequence":"first","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital"},{"name":"School of Respiratory Therapy, College of 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