Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation

D. Zhao, A. H. Besser, S. A. Wander, J. Sun, W. Zhou, B. Wang, T. Ince, M. A. Durante, W. Guo, G. Mills, D. Theodorescu, J. Slingerland

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64 Scopus citations

Abstract

p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.

Original languageEnglish (US)
Pages (from-to)5447-5459
Number of pages13
JournalOncogene
Volume34
Issue number43
DOIs
StatePublished - Oct 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhao, D., Besser, A. H., Wander, S. A., Sun, J., Zhou, W., Wang, B., Ince, T., Durante, M. A., Guo, W., Mills, G., Theodorescu, D., & Slingerland, J. (2015). Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. Oncogene, 34(43), 5447-5459. https://doi.org/10.1038/onc.2014.473