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P-cadherin is a direct PAX3–FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness

Oncogene volume 32, pages 1876–1887 (2013)Cite this article

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Abstract

Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood cancer of striated muscle characterized by the presence of the PAX3–FOXO1A or PAX7–FOXO1A chimeric oncogenic transcription factor. Identification of their targets is essential for understanding ARMS pathogenesis. To this aim, we analyzed transcriptomic data from rhabdomyosarcoma samples and found that P-cadherin expression is correlated with PAX3/7–FOXO1A presence. We then show that expression of a PAX3 dominant negative variant inhibits P-cadherin expression in ARMS cells. Using mouse models carrying modified Pax3 alleles, we demonstrate that P-cadherin is expressed in the dermomyotome and lies genetically downstream from the myogenic factor Pax3. Moreover, in vitro gel shift analysis and chromatin immunoprecipitation indicate that the P-cadherin gene is a direct transcriptional target for PAX3/7–FOXO1A. Finally, P-cadherin expression in normal myoblasts inhibits myogenesis and induces myoblast transformation, migration and invasion. Conversely, P-cadherin downregulation by small hairpin RNA decreases the transformation, migration and invasive potential of ARMS cells. P-cadherin also favors cadherin switching, which is a hallmark of metastatic progression, by controlling N- and M-cadherin expression and/or localization. Our findings demonstrate that P-cadherin is a direct PAX3–FOXO1A transcriptional target involved in ARMS aggressiveness. Therefore, P-cadherin emerges as a new and attractive target for therapeutic intervention in ARMS.

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Acknowledgements

We thank Vincent Mouly for the LHCN-M2 myoblasts, Setsuo Hirohashi and Keith Johnson for the P-cadherin cDNA, Mickael Rudnicki for the pBRIT plasmid, Pete Zammit for the pMSCV-Pax3-En-IRES-eGFP plasmids. We thank the Montpellier Imaging Facility (http://www.mri.cnrs.fr/) and Lionel Larue, Sophie Charrasse and Stéphane Bodin for discussion. This work was supported by the « Cartes d’Identite des Tumeurs » program (http://cit.ligue-cancer.net/) of the Ligue Nationale contre le Cancer, the Ligue Nationale contre le Cancer (LNCC) (« Equipe labellisée») and the Institut National du Cancer (INCa). CGR was supported by INSERM, ST by INCa and JLC by the Association pour la Recherche contre le Cancer (ARC). FR’s team is supported by the INSERM Avenir Program, Association Française Contre les Myopathies, LNCC, ARC, Fondation pour la Recherche Médicale, INCa and from the European Union Seventh Framework Programme, project ENDOSTEM (number 241440).

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  1. S Thuault and S Hayashi: These authors contributed equally to this work.

Authors and Affiliations

  1. Universités Montpellier 2 et 1, CRBM, CNRS, UMR 5237, Montpellier, France

    S Thuault, J Lagirand-Cantaloube, C Plutoni, F Comunale & C Gauthier-Rouvière

  2. UMRS787, INSERM-UPMC-AIM, Pitié-Salpétrière, Paris Cedex, France,

    S Hayashi & F Relaix

  3. INSERM Unité 830, Unité de Génétique Somatique, Institut Curie, Paris, France

    O Delattre

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Correspondence to C Gauthier-Rouvière.

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Thuault, S., Hayashi, S., Lagirand-Cantaloube, J. et al. P-cadherin is a direct PAX3–FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness. Oncogene 32, 1876–1887 (2013). https://doi.org/10.1038/onc.2012.217

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