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; G. Mills; D. Theodorescu; J. Slingerland

doi:10.1038/onc.2014.473

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, G. Mills, D. Theodorescu, J. Slingerland

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

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 language	English (US)
Pages (from-to)	5447-5459
Number of pages	13
Journal	Oncogene
Volume	34
Issue number	43
DOIs	https://doi.org/10.1038/onc.2014.473
State	Published - Oct 1 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

Access to Document

10.1038/onc.2014.473

Cite this

@article{955107eacd9c4d408ca7ddd9d4fa60e3,

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.",

author = "D. Zhao and Besser, {A. H.} and Wander, {S. A.} and J. Sun and W. Zhou and B. Wang and T. Ince and Durante, {M. A.} and W. Guo and G. Mills and D. Theodorescu and J. Slingerland",

year = "2015",

month = oct,

day = "1",

doi = "10.1038/onc.2014.473",

language = "English (US)",

volume = "34",

pages = "5447--5459",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "43",

}

TY - JOUR

T1 - Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation

AU - Zhao, D.

AU - Besser, A. H.

AU - Wander, S. A.

AU - Sun, J.

AU - Zhou, W.

AU - Wang, B.

AU - Ince, T.

AU - Durante, M. A.

AU - Guo, W.

AU - Mills, G.

AU - Theodorescu, D.

AU - Slingerland, J.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84945440732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945440732&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.473

DO - 10.1038/onc.2014.473

M3 - Article

C2 - 25684140

AN - SCOPUS:84945440732

SN - 0950-9232

VL - 34

SP - 5447

EP - 5459

JO - Oncogene

JF - Oncogene

IS - 43

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this