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

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.

• Authors: 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
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 6 Pg. 919-34 (Jun 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23666755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• POU4F1 protein, human
• RNA, Small Interfering
• Transcription Factor Brn-3A
• Tumor Suppressor Protein p53
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Apoptosis
• Cell Cycle Checkpoints
• Cell Line
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic
• Cellular Senescence
• DNA Breaks, Double-Stranded
• Humans
• Melanocytes (cytology, metabolism)
• Melanoma (metabolism, pathology)
• Proto-Oncogene Proteins B-raf (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Transcription Factor Brn-3A (antagonists & inhibitors, genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)