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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 34 Issue 43 Pg. 5447-59 (Oct 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25684140 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)