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Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer

Oncogene volume 32, pages 1351–1362 (2013)Cite this article

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Abstract

Expression of E-cadherin, a hallmark of epithelial–mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identified that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT, but also paves a way for the development of new treatment strategies against this disease.

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Abbreviations

BLBC:

basal-like breast cancer

ChIP:

chromatin immunoprecipitation

EMT:

epithelial–mesenchymal transition

LSD1:

lysine-specific demethylase 1

Suv39H1:

suppressor of variegation 3-9 homolog 1.

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Acknowledgements

We thank Dr Nathan L Vanderford for critical reading and editing of this manuscript. This work was supported by grants from NIH (RO1CA125454), Susan G Komen Foundation (KG081310), and Mary Kay Ash Foundation (to BP Zhou).

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, The University of Kentucky College of Medicine, Lexington, KY, USA

    C Dong, Y Wang, Y-I Chi, B M Evers & B P Zhou

  2. Markey Cancer Center, The University of Kentucky College of Medicine, Lexington, KY, USA

    C Dong, Y Wu, Y Wang, C Wang, P G Rychahou, B M Evers & B P Zhou

  3. Department of Molecular and Biomedical Pharmacology, The University of Kentucky College of Medicine, Lexington, KY, USA

    Y Wu

  4. Department of Biostatistics, The University of Kentucky College of Medicine, Lexington, KY, USA

    C Wang

  5. State Key Laboratory of Oncology in South China, Guangzhou, China

    T Kang

  6. Department of Surgery, The University of Kentucky College of Medicine, Lexington, KY, USA

    P G Rychahou & B M Evers

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Correspondence to B P Zhou.

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Dong, C., Wu, Y., Wang, Y. et al. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32, 1351–1362 (2013). https://doi.org/10.1038/onc.2012.169

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