title: Regulation of transcription factor Twist expression by the DNA architectural protein high mobility group A2 during epithelial-to-mesenchymal transition.
abstract: Deciphering molecular mechanisms that control epithelial-to-mesenchymal transition (EMT) contributes to our understanding of how tumor cells become invasive and competent for intravasation. We have established that transforming growth factor β activates Smad proteins, which induce expression of the embryonic factor high mobility group A2 (HMGA2), which causes mesenchymal transition. HMGA2 associates with Smad complexes and induces expression of an established regulator of EMT, the zinc finger transcription factor Snail. We now show that HMGA2 can also induce expression of a second regulator of EMT, the basic helix-loop-helix transcription factor Twist. Silencing of endogenous Twist demonstrated that this protein acts in a partially redundant manner together with Snail. Double silencing of Snail and Twist reverts mesenchymal HMGA2-expressing cells to a more epithelial phenotype when compared with single silencing of Snail or Twist. Furthermore, HMGA2 can directly associate with A:T-rich sequences and promote transcription from the Twist promoter. The new evidence proposes a model whereby HMGA2 directly induces multiple transcriptional regulators of the EMT program and, thus, is a potential biomarker for carcinomas displaying EMT during progression to more advanced stages of malignancy.
authors.affiliation: Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, Uppsala SE-751 24, Sweden.
authors.forename: E-Jean
authors.initials: EJ
authors.lastname: Tan
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thuault
authors.forename: Laia
authors.initials: L
authors.lastname: Caja
authors.forename: Tea
authors.initials: T
authors.lastname: Carletti
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse