title: 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.affiliation: Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hohenauer
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haferkamp
authors.forename: Daniela
authors.initials: D
authors.lastname: Senft
authors.forename: Claudia
authors.initials: C
authors.lastname: Kammerbauer
authors.forename: Sabine
authors.initials: S
authors.lastname: Fraschka
authors.forename: Saskia Anna
authors.initials: SA
authors.lastname: Graf
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Michael
authors.initials: M
authors.lastname: Flaig
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
authors.forename: Sabrina
authors.initials: S
authors.lastname: Höbel
authors.forename: Franziska
authors.initials: F
authors.lastname: Hoffmann
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050819:Transcription Factor Brn-3A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C494188:POU4F1 protein, human; D034741:RNA, Small Interfering; D050819:Transcription Factor Brn-3A; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf