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.
Document Type
Article
Publication Date
8-15-2014
Digital Object Identifier (DOI)
http://dx.doi.org/10.18632/oncotarget.2109
Funding Information
This work was supported in part by grants from NIH/NCI R01CA175105, NIH/NCATS UL1RR033173-KL2RR0033171 and ACS IRG85-001-22 to Q-B She.
Repository Citation
Cai, Weijia; Ye, Qing; and She, Qing-Bai, "Loss of 4E-BP1 Function Induces EMT and Promotes Cancer Cell Migration and Invasion via Cap-Dependent Translational Activation of Snail" (2014). Markey Cancer Center Faculty Publications. 52.
https://uknowledge.uky.edu/markey_facpub/52
Supplementary File
Notes/Citation Information
Published in Oncotarget, v. 5, no. 15, p. 6015-6027.
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