TGF-Β drives epithelial-mesenchymal transition through EF1-mediated downregulation of ESRP

K. Horiguchi, K. Sakamoto, D. Koinuma, Kentaro Senba, A. Inoue, S. Inoue, H. Fujii, A. Yamaguchi, K. Miyazawa, K. Miyazono, M. Saitoh

    Research output: Contribution to journalArticle

    104 Citations (Scopus)

    Abstract

    Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-Β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-Β-induced EMT, and found that TGF-Β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-Β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-Β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-Β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-Β-induced EMT and the progression of breast cancers.

    Original languageEnglish
    Pages (from-to)3190-3201
    Number of pages12
    JournalOncogene
    Volume31
    Issue number26
    DOIs
    Publication statusPublished - 2012 Jun 28

    Fingerprint

    Protein Splicing
    Epithelial-Mesenchymal Transition
    Transforming Growth Factors
    Down-Regulation
    Alternative Splicing
    Breast Neoplasms
    Fibroblast Growth Factor Receptors
    Microarray Analysis
    Tumor Cell Line
    Wound Healing
    Exons
    Protein Isoforms
    Proteins
    Up-Regulation
    Phenotype

    Keywords

    • δEMT
    • alternative splicing
    • breast cancer
    • dEF1
    • ESRP
    • TGF-β

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research
    • Genetics

    Cite this

    Horiguchi, K., Sakamoto, K., Koinuma, D., Senba, K., Inoue, A., Inoue, S., ... Saitoh, M. (2012). TGF-Β drives epithelial-mesenchymal transition through EF1-mediated downregulation of ESRP. Oncogene, 31(26), 3190-3201. https://doi.org/10.1038/onc.2011.493

    TGF-Β drives epithelial-mesenchymal transition through EF1-mediated downregulation of ESRP. / Horiguchi, K.; Sakamoto, K.; Koinuma, D.; Senba, Kentaro; Inoue, A.; Inoue, S.; Fujii, H.; Yamaguchi, A.; Miyazawa, K.; Miyazono, K.; Saitoh, M.

    In: Oncogene, Vol. 31, No. 26, 28.06.2012, p. 3190-3201.

    Research output: Contribution to journalArticle

    Horiguchi, K, Sakamoto, K, Koinuma, D, Senba, K, Inoue, A, Inoue, S, Fujii, H, Yamaguchi, A, Miyazawa, K, Miyazono, K & Saitoh, M 2012, 'TGF-Β drives epithelial-mesenchymal transition through EF1-mediated downregulation of ESRP', Oncogene, vol. 31, no. 26, pp. 3190-3201. https://doi.org/10.1038/onc.2011.493
    Horiguchi, K. ; Sakamoto, K. ; Koinuma, D. ; Senba, Kentaro ; Inoue, A. ; Inoue, S. ; Fujii, H. ; Yamaguchi, A. ; Miyazawa, K. ; Miyazono, K. ; Saitoh, M. / TGF-Β drives epithelial-mesenchymal transition through EF1-mediated downregulation of ESRP. In: Oncogene. 2012 ; Vol. 31, No. 26. pp. 3190-3201.
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