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

• Published in: EMBO molecular medicine Vol. 5; no. 6; pp. 919 - 934
• Main Authors: Hohenauer, Tobias, Berking, Carola, Schmidt, Andreas, Haferkamp, Sebastian, Senft, Daniela, Kammerbauer, Claudia, Fraschka, Sabine, Graf, Saskia Anna, Irmler, Martin, Beckers, Johannes, Flaig, Michael, Aigner, Achim, Höbel, Sabrina, Hoffmann, Franziska, Hermeking, Heiko, Rothenfusser, Simon, Endres, Stefan, Ruzicka, Thomas, Besch, Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2013; WILEY‐VCH Verlag; EMBO Press; WILEY-VCH Verlag; Springer Nature
• Subjects: Apoptosis; Brn-3 protein; Cell cycle; Cell Cycle Checkpoints; Cell growth; Cell Line; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cellular Senescence; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; Humans; Kinases; Melanocytes; Melanocytes - cytology; Melanocytes - metabolism; Melanoma; Melanoma - metabolism; Melanoma - pathology; MRE11 protein; Mutation; Neural crest; neural crest factors; p53 Protein; Proto-Oncogene Proteins B-raf - metabolism; Research Article; RNA Interference; RNA, Small Interfering - metabolism; RNA-mediated interference; Senescence; Signal transduction; Skin cancer; Transcription Factor Brn-3A - antagonists & inhibitors; Transcription Factor Brn-3A - genetics; Transcription Factor Brn-3A - metabolism; Tumor cell lines; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; tumourigenesis; apoptosis; melanoma; tumourigenesis; DNA damage; neural crest factors
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201201862

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.
Graphical Abstract
Brn3a, a POU family transcription factor normally involved in neuronal development, is reported here to promote melanoma survival by playing a role in cell cycle progression. Targeting Brn3a and its regulated genes could offer therapeutic value.