title: Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin.
abstract: Epidemiological studies have shown that most cases of lung cancers (85%-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, 1720 2nd Avenue South, 520 C, WTI, Birmingham, AL 35294, USA.
authors.forename: Nagaraj S
authors.initials: NS
authors.lastname: Nagathihalli
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Gonzalez
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
mesh_terms: D000107:Acetylation / Q000187:drug effects; D015703:Antigens, CD; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D012907:Smoking / Q000009:adverse effects*; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D001549:Benzamides; C513384:CDH1 protein, human; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D011725:Pyridines; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C118739:entinostat; D006655:Histone Deacetylases