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

研究成果: 雜誌貢獻文章

107 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)941-953
頁數13
期刊Molecular and Cellular Biology
32
發行號5
DOIs
出版狀態已發佈 - 三月 2012
對外發佈Yes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    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