title: Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis.
abstract: To metastasize, carcinoma cells must attenuate cell-cell adhesion to disseminate into distant organs. A group of transcription factors, including Twist1, Snail1, Snail2, ZEB1, and ZEB2, have been shown to induce epithelial mesenchymal transition (EMT), thus promoting tumor dissemination. However, it is unknown whether these transcription factors function independently or coordinately to activate the EMT program. Here we report that direct induction of Snail2 is essential for Twist1 to induce EMT. Snail2 knockdown completely blocks the ability of Twist1 to suppress E-cadherin transcription. Twist1 binds to an evolutionarily conserved E-box on the proximate Snail2 promoter to induce its transcription. Snail2 induction is essential for Twist1-induced cell invasion and distant metastasis in mice. In human breast tumors, the expression of Twist1 and Snail2 is highly correlated. Together, our results show that Twist1 needs to induce Snail2 to suppress the epithelial branch of the EMT program and that Twist1 and Snail2 act together to promote EMT and tumor metastasis.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California 92093-0636, USA.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Casas
authors.forename: Jihoon
authors.initials: J
authors.lastname: Kim
authors.forename: Andrés
authors.initials: A
authors.lastname: Bendesky
authors.forename: Lucila
authors.initials: L
authors.lastname: Ohno-Machado
authors.forename: Cecily J
authors.initials: CJ
authors.lastname: Wolfe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000502:physiology*; D016133:Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse