title: Loss of 4E-BP1 function induces EMT and promotes cancer cell migration and invasion via cap-dependent translational activation of snail.
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.
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA. Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA. These authors contributed equally to this work.
authors: Weijia
authors: W
authors: Cai
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA. Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA. These authors contributed equally to this work.
authors: Qing
authors: Q
authors: Ye
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA. Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors: Qing-Bai
authors: QB
authors: She
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors