The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival

Authors

  • Tobias Hohenauer,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Carola Berking,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Andreas Schmidt,

    1. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
    2. Center of Integrated Protein Science CIPS-M at the Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
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  • Sebastian Haferkamp,

    1. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
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  • Daniela Senft,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Claudia Kammerbauer,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Sabine Fraschka,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Saskia Anna Graf,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Martin Irmler,

    1. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Neuherberg, Germany
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  • Johannes Beckers,

    1. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Neuherberg, Germany
    2. Technical University Munich, Center of Life and Food Sciences Weihenstephan, Freising, Germany
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  • Michael Flaig,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Achim Aigner,

    1. Institute of Pharmacology, Philipps-University, Faculty of Medicine, Marburg, Germany
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  • Sabrina Höbel,

    1. Institute of Pharmacology, Philipps-University, Faculty of Medicine, Marburg, Germany
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  • Franziska Hoffmann,

    1. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
    2. Center of Integrated Protein Science CIPS-M at the Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
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  • Heiko Hermeking,

    1. Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilian University, Munich, Germany
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  • Simon Rothenfusser,

    1. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
    2. Center of Integrated Protein Science CIPS-M at the Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
    3. Section of Gastroenterology and Endocrinology, Medizinische Klinik Innenstadt, Ludwig-Maximilian University, Munich, Germany
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  • Stefan Endres,

    1. Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
    2. Center of Integrated Protein Science CIPS-M at the Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University, Munich, Germany
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  • Thomas Ruzicka,

    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
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  • Robert Besch

    Corresponding author
    1. Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany
    • Tel.: +49 89 5160 6365; Fax: +49 89 5160 6366

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Abstract

Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis.

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