The Aurora-A-Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma

Jing Wang, Kumar Nikhil, Keith Viccaro, Lei Chang, Max Jacobsen, George Sandusky, Kavita Shah

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

We uncovered a crucial role for the Aurora kinase A (AURKA)- Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation - AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors in vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.

Original languageEnglish (US)
Pages (from-to)1078-1093
Number of pages16
JournalJournal of cell science
Volume130
Issue number6
DOIs
StatePublished - Jan 1 2017

Keywords

  • AURKA
  • Drug discovery
  • EMT
  • Pancreatic cancer
  • Therapy
  • Twist1

ASJC Scopus subject areas

  • Cell Biology

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