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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-122193
  • 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 signallingPigment 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.show moreshow less

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Metadaten
Author: Tobias Hohenauer, Carola Berking, Andreas Schmidt, Sebastian Haferkamp, Daniela Senft, Claudia Kammerbauer, Sabine Fraschka, Saskia Anna Graf, Martin Irmler, Johannes Beckers, Michael Flaig, Achim Aigner, Sabrina Höbel, Franziska Hoffmann, Heiko Hermeking, Simon Rothenfusser, Stefan Endres, Thomas Ruzicka, Robert Besch
URN:urn:nbn:de:bvb:20-opus-122193
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Language:English
Parent Title (English):EMBO Molecular Medicine
ISSN:1757-4676
Year of Completion:2013
Volume:5
Pagenumber:919-934
Source:EMBO Molecular Medicine (2013) 5, 919–934. DOI 10.1002/emmm.201201862
DOI:https://doi.org/10.1002/emmm.201201862
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 572 Biochemie
Tag:BRAF mutations; BRN-3A; DNA; DNA damage; P53; apoptosis; domain; family; in-vitro; melanoma; neural crest factors; oncogene-induced senescence; tumourigenesis
Release Date:2016/02/25
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung