title: Chidamide alleviates TGF-β-induced epithelial-mesenchymal transition in lung cancer cell lines.
abstract: Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis.
authors.affiliation: Institute of Biomedical Science, College of Life Sciences, National Chung Hsing University, 250, Guoguang Road, Taichung, 40227, Taiwan.|Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Bing-Yen
authors.initials: BY
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Science, College of Life Sciences, National Chung Hsing University, 250, Guoguang Road, Taichung, 40227, Taiwan.|Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.|Department of Respiratory Care, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Ching-Hsiung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute of Medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung, 40203, Taiwan.
authors.forename: Peng-Ju
authors.initials: PJ
authors.lastname: Chien
authors.affiliation: Institute of Medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung, 40203, Taiwan.
authors.forename: Yueh-Feng
authors.initials: YF
authors.lastname: Wu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung, 40203, Taiwan. jlko@csmu.edu.tw.|Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan. jlko@csmu.edu.tw.
authors.forename: Jiunn-Liang
authors.initials: JL
authors.lastname: Ko
authors.affiliation: Institute of Biomedical Science, College of Life Sciences, National Chung Hsing University, 250, Guoguang Road, Taichung, 40227, Taiwan. jwchen@dragon.nchu.edu.tw.
authors.forename: Jeremy J W
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D000631:Aminopyridines / Q000494:pharmacology*; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D000631:Aminopyridines; D015703:Antigens, CD; D000970:Antineoplastic Agents; D001549:Benzamides; C513384:CDH1 protein, human; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D016212:Transforming Growth Factor beta; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
keywords: Chidamide; Epithelial–mesenchymal transition; TGF-β