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

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107 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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Liu, Y. N., Abou-Kheir, W., Yin, J. J., 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, 32(5), 941-953. https://doi.org/10.1128/MCB.06306-11