title: Tranilast Inhibits Genes Functionally Involved in Cell Proliferation, Fibrosis, and Epigenetic Regulation and Epigenetically Induces miR-29c Expression in Leiomyoma Cells.
abstract: Tranilast (N-3,4-dimethoxycinnamoyl anthranilic acid) is an antiallergic agent with inhibitory effects on cell proliferation and extracellular matrix production. Here we assess the effect of tranilast on the expression of miR-29c and genes functionally involved in cell proliferation, fibrosis, and epigenetic regulation in isolated leiomyoma smooth muscle cells (LSMC). Tranilast significantly inhibited the rate of LSMC proliferation, which was associated with downregulation of cell cycle progression genes cyclin D1 (CCND1) and cyclin-dependent kinase 2 (CDK2) expression at messenger RNA and protein levels ( P < .05). Tranilast also suppressed the expression of collagen type I (COL1), collagen type III alpha 1 chain (COL3A1), the profibrotic cytokine, transforming growth factor β-3 (TGF-β3), DNA (cytosine-5)-methyltransferase 1 (DNMT1), and enhancer of zeste homolog 2 (EZH2), which regulate epigenetic status of gene promoters ( P < .05). Tranilast also significantly induced the expression of cellular and secreted miR-29c through downregulation of methylation status of miR-29c promoter ( P < .05). In addition, tranilast suppressed the activity of luciferase reporter containing 3'UTR of COL3A1 and CDK2, which are downstream targets of miR-29c ( P < .05). Knockdown of miR-29c expression attenuated the inhibitory effects of tranilast on COL3A1 and CDK2 protein expression ( P < .05). Collectively, these findings suggest that tranilast could have therapeutic potential as an inhibitory agent for leiomyoma growth and its associated symptoms.
authors.affiliation: 1 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center and LA Biomed Research Institute, Torrance, CA, USA.
authors.forename: Tsai-Der
authors.initials: TD
authors.lastname: Chuang
authors.affiliation: 1 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center and LA Biomed Research Institute, Torrance, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Khorram
mesh_terms: D018926:Anti-Allergic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D018926:Anti-Allergic Agents; D024042:Collagen Type I; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D062367:ortho-Aminobenzoates; C012293:tranilast
keywords: CCND1; CDK2; DNMT1; EZH2; TGF-β3; collagen type I; collagen type III; miR-29c; promoter methylation; tranilast