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.
Highlights
Characteristic properties of cancer cells, such as increased cell proliferation, survival or cell migration, are essential for embryonic development
Brn3a is expressed in human melanoma, but not in melanocytes and other non-malignant skin cells Brn3a expression was analysed in human melanoma cell lines and in non-malignant skin cells
We demonstrate that the POU domain transcription factor Brn3a, normally expressed in neural crest cells, is expressed in melanoma
Summary
Characteristic properties of cancer cells, such as increased cell proliferation, survival or cell migration, are essential for embryonic development. Lineage-specific re-expression of such factors can characterize certain cancer types and is of potential therapeutic value. Multipotent neural crest cells become progressively restricted to specific sub-lineages, including neuronal cell types, endocrine cells and melanocytic cells (Crane & Trainor, 2006). In neuroectodermal tumours as well as in melanoma, a deregulated expression of neuronal factors normally expressed in neural crest cells may contribute ß 2013 The Authors.
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