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, Gordon Mills, D. Theodorescu, J. Slingerland

Research output: Contribution to journalArticle

60 Citations (Scopus)

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
Externally publishedYes

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STAT3 Transcription Factor
Epithelial-Mesenchymal Transition
Up-Regulation
Neoplasm Metastasis
Neoplasms
Phosphatidylinositol 3-Kinases
Janus Kinase 2
Threonine
Urinary Bladder Neoplasms
Transcriptional Activation
Cell Cycle
Breast
Epithelial Cells
Maintenance
Phosphorylation
Breast Neoplasms
Growth

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., ... 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

Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. / Zhao, D.; Besser, A. H.; Wander, S. A.; Sun, J.; Zhou, W.; Wang, B.; Ince, T.; Durante, M. A.; Guo, W.; Mills, Gordon; Theodorescu, D.; Slingerland, J.

In: Oncogene, Vol. 34, No. 43, 01.10.2015, p. 5447-5459.

Research output: Contribution to journalArticle

Zhao, D, Besser, AH, Wander, SA, Sun, J, Zhou, W, Wang, B, Ince, T, Durante, MA, Guo, W, Mills, G, Theodorescu, D & Slingerland, J 2015, 'Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation', Oncogene, vol. 34, no. 43, pp. 5447-5459. https://doi.org/10.1038/onc.2014.473
Zhao, D. ; Besser, A. H. ; Wander, S. A. ; Sun, J. ; Zhou, W. ; Wang, B. ; Ince, T. ; Durante, M. A. ; Guo, W. ; Mills, Gordon ; Theodorescu, D. ; Slingerland, J. / Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. In: Oncogene. 2015 ; Vol. 34, No. 43. pp. 5447-5459.
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