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STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression

Oncogene volume 35, pages 1049–1057 (2016)Cite this article

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Abstract

The epithelial–mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor β (TGF-β) in certain kinds of cancer cells through the induction of Snail, a key regulator of EMT. We have previously found that TGF-β remarkably induces Snail expression in cooperation with Ras signals; however, the underlying mechanism of this synergism has not yet been determined. Here, we demonstrate that signal transducer and activator of transcription 3 (STAT3) acts as a mediator that synergizes TGF-β and Ras signals. The overexpression of STAT3 enhanced Snail induction, whereas siRNA-mediated knockdown of STAT3 inhibited it. The STAT3-YF mutant, which has Tyr 705 substituted with Phe, did not enhance Snail induction. Several STAT3 mutants lacking transcriptional activity also failed to enhance it; however, the putative STAT3-binding elements in the Snail promoter regions were not required for STAT3-mediated Snail induction. Protein inhibitor of activated STAT3 (PIAS3) inhibited the enhanced Snail promoter activity induced by TGF-β and Ras. The interaction between PIAS3 and STAT3 was reduced by TGF-β in cells harboring oncogenic Ras, whereas TGF-β promoted the binding of PIAS3 to Smad3, a crucial mediator of TGF-β signaling. Therefore, these findings suggest that STAT3 enhances Snail induction when it is dissociated from PIAS3 by TGF-β in cooperation with Ras signals.

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Acknowledgements

We would like to thank M Myogahara for her excellent secretarial assistance. We also thank Dr T Shirakihara, Dr K Horiguchi, Dr D Koinuma, Dr S Ehata, Dr H Suzuki, and Dr K Miyazono for their helpful advice. This work was supported by JSPS KAKENHI Grant Number 24390419, the JSPS Core-to-Core Program ‘Cooperative International Framework in TGF-β Family Signaling’, and a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was also supported by Astellas Foundation for Research on Metabolic Disorders (to MS) and research grants from the Fugaku Trust for Medicinal Research, the Mitsubishi Foundation, and Terumo Life Science Foundation (to KM). This work was supported by JSPS KAKENHI Grant Number 24390419, the JSPS Core-to-Core Program ‘Cooperative International Framework in TGF-β Family Signaling’, and a research program of the Project for the Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was also supported by Astellas Foundation for Research on Metabolic Disorders (to MS) and research grants from the Fugaku Trust for Medicinal Research, the Mitsubishi Foundation and Terumo Life Science Foundation (to KM).

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Authors and Affiliations

  1. Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan,

    M Saitoh, K Endo, S Furuya, M Minami, A Fukasawa & K Miyazawa

  2. Research Training Program for Undergraduates, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan,

    S Furuya & M Minami

  3. Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Ehime, Japan

    T Imamura

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  1. M Saitoh
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Correspondence to M Saitoh.

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Saitoh, M., Endo, K., Furuya, S. et al. STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression. Oncogene 35, 1049–1057 (2016). https://doi.org/10.1038/onc.2015.161

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