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

Oncogene. 2015 Oct;34(43):5447-59. doi: 10.1038/onc.2014.473. Epub 2015 Feb 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cytoplasm / genetics*
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • HEK293 Cells
  • Humans
  • Janus Kinase 2 / genetics
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis / genetics*
  • Nuclear Proteins / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Proliferating Cell Nuclear Antigen / genetics*
  • Promoter Regions, Genetic / genetics
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / genetics
  • Twist-Related Protein 1 / genetics*
  • Up-Regulation / genetics*
  • Urinary Bladder Neoplasms / genetics


  • Nuclear Proteins
  • Proliferating Cell Nuclear Antigen
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • p27 antigen
  • Phosphatidylinositol 3-Kinases
  • JAK2 protein, human
  • Janus Kinase 2