Oncotarget

Research Papers:

TLE1 inhibits anoikis and promotes tumorigenicity in human lung cancer cells through ZEB1-mediated E-cadherin repression

Xin Yao, Tri Pham, Brandi Temple, Selena Gray, Cornita Cannon, Camry Hardy, Kamari Fletcher, Shubha Kale Ireland, Ahamed Hossain, Renwei Chen, Asim B. Abdel-Mageed and Hector Biliran _

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Oncotarget. 2017; 8:72235-72249. https://doi.org/10.18632/oncotarget.19703

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Abstract

Xin Yao1, Tri Pham1, Brandi Temple1, Selena Gray1, Cornita Cannon1, Camry Hardy1, Kamari Fletcher1, Shubha Kale Ireland1, Ahamed Hossain1, Renwei Chen2, Asim B. Abdel-Mageed3 and Hector Biliran1

1Department of Biological and Public Health Sciences, Xavier University of Louisiana, New Orleans, LA 70125, USA

2Center for Bioengineering, University of California, Santa Barbara, CA 93106, USA

3Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA

Correspondence to:

Hector Biliran, email: [email protected]

Keywords: TLE1, anoikis, E-cadherin, tumorigenecity, ZEB1

Received: April 27, 2017     Accepted: June 26, 2017     Published: July 31, 2017

ABSTRACT

The Transducin-like enhancer of split 1 (TLE1) corepressor protein is overexpressed in human lung tumors and is a putative lung-specific oncogene. However, the molecular mechanism underlying its oncogenic function remains to be delineated. Here, we report an important role of TLE1 in promoting lung tumorigenesis by a mechanism involving induction of anoikis resistance. Using the human lung adenocarcinoma A549 and immortalized bronchial epithelial BEAS-2B cell lines, we observed that TLE1 inhibits anoikis through transcriptional repression of E-cadherin gene. In support of E-cadherin as a downstream target of TLE1 to block anoikis, forced expression of E-cadherin attenuated TLE1-induced anoikis resistance while E-cadherin downregulation decreased the anoikis sensitivity of TLE1 knockdown cells. Furthermore, we determined that E-cadherin expression is transcriptionally induced upon loss of cell attachment and functions as an effector of anoikis. Loss of E-cadherin via the siRNA strategy or exogenous TLE1 expression was sufficient to attenuate anoikis in A549 and BEAS-2B cells. Importantly, we demonstrated that the ZEB1 transcriptional factor is required for TLE1-mediated E-cadherin repression and anoikis resistance. ZEB1 interacted with and recruited the TLE1 to the E-cadherin promoter to impose histone deacetylation and gene silencing. In vivo, TLE1 strongly promoted tumorigenicity of A549 cells in a ZEB1-dependent manner. Underscoring its role in anoikis insensitivity of lung cancer cells, the TLE1-mediated E-cadherin repression was negatively regulated by the tumor suppressor Bcl-2 inhibitor of transcription 1 (Bit1) to effect anoikis. These findings identify the ZEB1/TLE1/E-cadherin transcriptional mechanism as a novel pathway that promotes anoikis resistance and oncogenicity of lung cancer cells.


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