TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin

Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):277-84. doi: 10.1016/j.bbrc.2014.11.007. Epub 2014 Nov 15.

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.

Keywords: Anoikis; Bit1; E-cadherin; EMT; Survival; TLE1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Anoikis
  • Antigens, CD
  • Cadherins / metabolism*
  • Carboxylic Ester Hydrolases / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Co-Repressor Proteins
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylases / metabolism
  • Humans
  • Lung Neoplasms / metabolism*
  • Mitochondrial Proteins / metabolism
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Transcription, Genetic

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Co-Repressor Proteins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • TLE1 protein, human
  • Carboxylic Ester Hydrolases
  • PTH2 protein, human
  • Histone Deacetylases