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, Tan Ince, M. A. Durante, W. Guo, G. Mills, D. Theodorescu, Joyce M Slingerland

Research output: Contribution to journalArticle

54 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)5447-5459
Number of pages13
JournalOncogene
Volume34
Issue number43
DOIs
StatePublished - Feb 16 2015

Fingerprint

STAT3 Transcription Factor
Epithelial-Mesenchymal Transition
Up-Regulation
Neoplasm Metastasis
Neoplasms
Phosphatidylinositol 3-Kinases
Janus Kinase 2
Threonine
Urinary Bladder Neoplasms
Transcriptional Activation
Cell Cycle
Breast
Epithelial Cells
Maintenance
Phosphorylation
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. / Zhao, D.; Besser, A. H.; Wander, S. A.; Sun, J.; Zhou, W.; Wang, B.; Ince, Tan; Durante, M. A.; Guo, W.; Mills, G.; Theodorescu, D.; Slingerland, Joyce M.

In: Oncogene, Vol. 34, No. 43, 16.02.2015, p. 5447-5459.

Research output: Contribution to journalArticle

Zhao, D, Besser, AH, Wander, SA, Sun, J, Zhou, W, Wang, B, Ince, T, Durante, MA, Guo, W, Mills, G, Theodorescu, D & Slingerland, JM 2015, 'Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation', Oncogene, vol. 34, no. 43, pp. 5447-5459. https://doi.org/10.1038/onc.2014.473
Zhao, D. ; Besser, A. H. ; Wander, S. A. ; Sun, J. ; Zhou, W. ; Wang, B. ; Ince, Tan ; Durante, M. A. ; Guo, W. ; Mills, G. ; Theodorescu, D. ; Slingerland, Joyce M. / Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. In: Oncogene. 2015 ; Vol. 34, No. 43. pp. 5447-5459.
@article{18a5339aef2d49c79c86c7516c0ba5a2,
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 Tan Ince and Durante, {M. A.} and W. Guo and G. Mills and D. Theodorescu and Slingerland, {Joyce M}",
year = "2015",
month = "2",
day = "16",
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, Tan

AU - Durante, M. A.

AU - Guo, W.

AU - Mills, G.

AU - Theodorescu, D.

AU - Slingerland, Joyce M

PY - 2015/2/16

Y1 - 2015/2/16

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

VL - 34

SP - 5447

EP - 5459

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 43

ER -