title: 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: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: D
authors: D
authors: Zhao
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: A H
authors: AH
authors: Besser
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: S A
authors: SA
authors: Wander
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: J
authors: J
authors: Sun
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: W
authors: http://orcid.org/0000-0002-5496-5815
authors: W
authors: Zhou
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: B
authors: B
authors: Wang
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Pathology, Stem Cell Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: T
authors: T
authors: Ince
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: M A
authors: MA
authors: Durante
authors: Department of Bioinformatics and Computational Biology, and Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors: W
authors: W
authors: Guo
authors: Department of Bioinformatics and Computational Biology, and Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors: G
authors: G
authors: Mills
authors: University of Colorado Cancer Center, University of Colorado, Aurora, CO, USA.
authors: D
authors: D
authors: Theodorescu
authors: Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: J
authors: J
authors: Slingerland
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C413374:p27 antigen; D019869:Phosphatidylinositol 3-Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2