Oncotarget

Research Papers:

Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail

Weijia Cai, Qing Ye and Qing-Bai She _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:6015-6027. https://doi.org/10.18632/oncotarget.2109

Metrics: PDF 2161 views  |   HTML 2293 views  |   ?  


Abstract

Weijia Cai1,2,*, Qing Ye1,2,* and Qing-Bai She1,2

1 Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA

2 Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA

* These authors contributed equally to this work

Correspondence:

Qing-Bai She, email:

Keywords: 4E-BP1, mTORC1, Snail, EMT, migration, invasion

Received: March 6, 2014 Accepted: June 15, 2014 Published: June 16, 2014

Abstract

The cap-dependent translation is frequently deregulated in a variety of cancers associated with tumor progression. However, the molecular basis of the translation activation for metastatic progression of cancer remains largely elusive. Here, we demonstrate that activation of cap-dependent translation by silencing the translational repressor 4E-BP1 causes cancer epithelial cells to undergo epithelial-mesenchymal transition (EMT), which is associated with selective upregulation of the EMT inducer Snail followed by repression of E-cadherin expression and promotion of cell migratory and invasive capabilities as well as metastasis. Conversely, inhibition of cap-dependent translation by a dominant active mutant 4E-BP1 effectively downregulates Snail expression and suppresses cell migration and invasion. Furthermore, dephosphorylation of 4E-BP1 by mTORC1 inhibition or directly targeting the translation initiation also profoundly attenuates Snail expression and cell motility, whereas knockdown of 4E-BP1 or overexpression of Snail significantly rescues the inhibitory effects. Importantly, 4E-BP1-regulated Snail expression is not associated with its changes in the level of transcription or protein stability. Together, these findings indicate a novel role of 4E-BP1 in the regulation of EMT and cell motility through translational control of Snail expression and activity, and suggest that targeting cap-dependent translation may provide a promising approach for blocking Snail-mediated metastatic potential of cancer.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2109