title: TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin.
abstract: The Groucho transcriptional corepressor TLE1 protein has recently been shown to be a putative lung specific oncogene, but its underlying oncogenic activity in lung cancer has not been fully elucidated. In this report, we investigated whether TLE1 regulates lung cancer aggressiveness using the human lung adenocarcinoma cell line A549 as a model system. Through a combination of genetic approaches, we found that TLE1 potentiates epithelial-to-mesenchymal transition (EMT) in A549 cells in part through suppression of the tumor suppressor gene E-cadherin. Exogenous expression of TLE1 in A549 cells resulted in heightened EMT phenotypes (enhanced fibroblastoid morphology and increased cell migratory potential) and in molecular alterations characteristic of EMT (downregulation of the epithelial marker E-cadherin and upregulation of the mesenchymal marker Vimentin). Conversely, downregulation of endogenous TLE1 expression in these cells resulted in reversal of basal EMT characterized by a cuboidal-like epithelial cell phenotype, reduced cell motility, and upregulated E-cadherin expression. Mechanistic studies showed that TLE1 suppresses E-cadherin expression at the transcriptional level in part by recruiting histone deacetylase (HDAC) activity to the E-cadherin promoter. Consistently, the HDAC inhibitor TSA partially reversed the TLE1-induced E-cadherin downregulation and cell migration, suggesting a role for HDACs in TLE1-mediated transcriptional repression of E-cadherin and EMT function. These findings uncover a novel role of TLE1 in regulating EMT in A549 cells through its repressive effect on E-cadherin and provide a mechanism for TLE1 oncogenic activity in lung cancer.
authors.affiliation: Department of Biology, Xavier University of Louisiana,1 Drexel Drive, New Orleans, LA 70125, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Biology, Xavier University of Louisiana,1 Drexel Drive, New Orleans, LA 70125, United States.
authors.forename: Shubha Kale
authors.initials: SK
authors.lastname: Ireland
authors.affiliation: Department of Biology, Xavier University of Louisiana,1 Drexel Drive, New Orleans, LA 70125, United States.
authors.forename: Tri
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Biology, Xavier University of Louisiana,1 Drexel Drive, New Orleans, LA 70125, United States.
authors.forename: Brandi
authors.initials: B
authors.lastname: Temple
authors.affiliation: Center for Nanomedicine, Sanford-Burnham Medical Research Institute, 1105 Life Sciences Technology Bldg., University of California, Santa Barbara, CA 93106, United States.
authors.forename: Renwei
authors.initials: R
authors.lastname: Chen
authors.affiliation: Stanley S. Scott Cancer Center and Department of Obstetrics & Gynecology, Louisiana Health Sciences Center, United States.
authors.forename: Madhwa H G
authors.initials: MH
authors.lastname: Raj
authors.affiliation: Department of Biology, Xavier University of Louisiana,1 Drexel Drive, New Orleans, LA 70125, United States. Electronic address: hbiliran@xula.edu.
authors.forename: Hector
authors.initials: H
authors.lastname: Biliran
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D023102:Anoikis; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D056970:Co-Repressor Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C499043:TLE1 protein, human; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human; D006655:Histone Deacetylases
keywords: Anoikis; Bit1; E-cadherin; EMT; Survival; TLE1