title: RAC1 activation mediates Twist1-induced cancer cell migration.
abstract: Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Yang
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C107953:RAC1 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D020830:rac1 GTP-Binding Protein