Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.
D ZhaoA H BesserS A WanderJ SunWen ZhouB WangT InceM A DuranteW GuoG MillsD TheodorescuJ SlingerlandPublished in: Oncogene (2015)
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.
Keyphrases
- squamous cell
- epithelial mesenchymal transition
- cell proliferation
- signaling pathway
- transforming growth factor
- cell cycle
- transcription factor
- induced apoptosis
- squamous cell carcinoma
- dna methylation
- poor prognosis
- endothelial cells
- pi k akt
- small cell lung cancer
- protein kinase
- immune response
- machine learning
- inflammatory response
- toll like receptor
- binding protein
- cell death
- nuclear factor
- cell migration
- muscle invasive bladder cancer