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SND1 acts as a novel gene transcription activator recognizing the conserved Motif domains of Smad promoters, inducing TGFβ1 response and breast cancer metastasis

Oncogene volume 36, pages 3903–3914 (2017)Cite this article

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Abstract

As an AEG-1/MTDH/LYRIC-binding protein, Staphylococcal nuclease domain-containing 1 (SND1) is upregulated in numerous human cancers where it has been assigned multiple functional roles. In this study, we discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1 (TGFβ1) signaling pathway, which promotes metastasis in breast cancer. We illustrated that SND1 physically associated with and recruited the histone acetylase GCN5 to the promoter regions of Smad2/3/4, and consequently enhanced the gene transcriptional activation of Smad2/3/4, which are essential downstream regulators in the TGFβ1 pathway. An electrophoretic mobility shift assay experiment further verified that SND1 could recognize the conserved domains (motifs 1 and 2) in the promoter regions of the Smad genes. Glutathione S-transferase (GST) pulldown assays indicated that the tudor domain of SND1 was responsible for the recruitment of GCN5, which increased histone H3K9 acetylation. Consistent with these results, a loss-of-function of SND1 reduced the protein level of Smads and the phosphorylation of R-Smads, thereby attenuating the R-Smad/Co-Smad depended transcription and, as a result, inhibited TGFβ signaling activation.

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Acknowledgements

This work was supported by grant from the National Science Foundation for Distinguished Young Scholars of China (31125012 to JY), grants from the National Natural Science Foundation of China (81202102 and 81672592 to LY, 31370749 and 31670759 to JY and 81572882 to ZY), grant from Project for Innovative Research Team of Ministry of Education (IRT13085 to JY), grants from Project of Applicative Basic Research and Advanced Technology of Tianjin Municipal Science and Technology Commission (13JCQNJC12100 to LY) and grant from Specialized Research Fund for the Doctoral Program of Higher Education (20121202120018 to LY).

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  1. L Yu and Y Di: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China

    L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang & J Yang

  2. Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang, Z Yao & J Yang

  3. Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University,, Tianjin, China

    L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang, Z Yao & J Yang

  4. Key Laboratory of the Educational Ministry of China, Tianjin Medical University,, Tianjin, China

    L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang, Z Yao & J Yang

  5. Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China

    L Yu, Y Di, L Xin, Y Ren, X Liu, X Sun, W Zhang, Z Yao & J Yang

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Yu, L., Di, Y., Xin, L. et al. SND1 acts as a novel gene transcription activator recognizing the conserved Motif domains of Smad promoters, inducing TGFβ1 response and breast cancer metastasis. Oncogene 36, 3903–3914 (2017). https://doi.org/10.1038/onc.2017.30

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