title: Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis.
abstract: Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a function-based genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.
authors.forename: M A
authors.initials: MA
authors.lastname: Smit
authors.forename: D S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D034622:RNA Interference; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C000630720:ZEB1 protein, rat; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020813:Receptor, trkB