Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition

Yen Nien Liu, Wassim Abou-Kheir, Juan Juan Yin, Lei Fang, Paul Hynes, Orla Casey, Dong Hu, Yong Wan, Victoria Seng, Heather Sheppard-Tillman, Philip Martin, Kathleen Kelly

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factorβ (TGFβ)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFβ-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

Original languageEnglish
Pages (from-to)941-953
Number of pages13
JournalMolecular and Cellular Biology
Volume32
Issue number5
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Transforming Growth Factors
Prostatic Neoplasms
Prostate
Tissue Array Analysis
Gastropoda
Pathologic Processes
Hyperplasia
Carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. / Liu, Yen Nien; Abou-Kheir, Wassim; Yin, Juan Juan; Fang, Lei; Hynes, Paul; Casey, Orla; Hu, Dong; Wan, Yong; Seng, Victoria; Sheppard-Tillman, Heather; Martin, Philip; Kelly, Kathleen.

In: Molecular and Cellular Biology, Vol. 32, No. 5, 03.2012, p. 941-953.

Research output: Contribution to journalArticle

Liu, YN, Abou-Kheir, W, Yin, JJ, Fang, L, Hynes, P, Casey, O, Hu, D, Wan, Y, Seng, V, Sheppard-Tillman, H, Martin, P & Kelly, K 2012, 'Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition', Molecular and Cellular Biology, vol. 32, no. 5, pp. 941-953. https://doi.org/10.1128/MCB.06306-11
Liu, Yen Nien ; Abou-Kheir, Wassim ; Yin, Juan Juan ; Fang, Lei ; Hynes, Paul ; Casey, Orla ; Hu, Dong ; Wan, Yong ; Seng, Victoria ; Sheppard-Tillman, Heather ; Martin, Philip ; Kelly, Kathleen. / Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 5. pp. 941-953.
@article{2dc322ba9047472882aaacc6b07c4a8e,
title = "Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition",
abstract = "Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factorβ (TGFβ)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFβ-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.",
author = "Liu, {Yen Nien} and Wassim Abou-Kheir and Yin, {Juan Juan} and Lei Fang and Paul Hynes and Orla Casey and Dong Hu and Yong Wan and Victoria Seng and Heather Sheppard-Tillman and Philip Martin and Kathleen Kelly",
year = "2012",
month = "3",
doi = "10.1128/MCB.06306-11",
language = "English",
volume = "32",
pages = "941--953",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition

AU - Liu, Yen Nien

AU - Abou-Kheir, Wassim

AU - Yin, Juan Juan

AU - Fang, Lei

AU - Hynes, Paul

AU - Casey, Orla

AU - Hu, Dong

AU - Wan, Yong

AU - Seng, Victoria

AU - Sheppard-Tillman, Heather

AU - Martin, Philip

AU - Kelly, Kathleen

PY - 2012/3

Y1 - 2012/3

N2 - Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factorβ (TGFβ)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFβ-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

AB - Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. In a model of transforming growth factorβ (TGFβ)-induced prostatic EMT, SLUG is the dominant regulator of EMT initiation in vitro and in vivo, as demonstrated by the inhibition of EMT following Slug depletion. In contrast, SNAIL depletion was significantly less rate limiting. TGFβ-stimulated KLF4 degradation is required for SLUG induction. Expression of a degradation-resistant KLF4 mutant inhibited EMT, and furthermore, depletion of Klf4 was sufficient to initiate SLUG-dependent EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. Furthermore, self-reinforcing regulatory loops for SLUG-KLF4 and SLUG-FOXA1 lead to SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters, silencing transcription and consolidating mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced-stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

UR - http://www.scopus.com/inward/record.url?scp=84863160718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863160718&partnerID=8YFLogxK

U2 - 10.1128/MCB.06306-11

DO - 10.1128/MCB.06306-11

M3 - Article

VL - 32

SP - 941

EP - 953

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 5

ER -