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Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation

Oncogene volume 33, pages 2363–2374 (2014)Cite this article

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Abstract

Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer metastasis.

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Acknowledgements

We thank Dr MT Teh, Professor K Parkinson, Dr SM Tsang, Dr MS Ikram and members of CDOS for helpful discussion and technical assistance. This work was supported by a British Skin Foundation-funded studentship awarded to HW and in part by the Institute of Dentistry as well as The Facial Surgery Research Foundation-Saving Faces.

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  1. Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK

    L Brown, A Waseem, J Szary, E Gunic, T Mannan, M Unadkat & H Wan

  2. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK

    I N Cruz & M Yang

  3. Division of Biomedical Sciences, St George’s, University of London, Cranmer Terrace, London, UK

    F Valderrama

  4. Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Cutaneous Research, Blizard Institute, London, UK

    E A O′Toole

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Brown, L., Waseem, A., Cruz, I. et al. Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation. Oncogene 33, 2363–2374 (2014). https://doi.org/10.1038/onc.2013.186

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