BRN2

BRN2 (BRN2 stands for Brain-2) is a transcription factor of the POU family that plays a key role in neuroendocrine and melanocytic development and differentiation. The POU family is a group of transcription factors with a highly conserved homeodomain. Fifteen POU genes have been found in the human genome. The POU family of domains plays a central role in embryogenesis and is highly expressed in the cells of the neural crest and the developing brain.

BRN2 is encoded by the POU3F2 gene (chromosome 6q16) and was first described in the central nervous system (CNS) in 1989.

BRN2 is not only a central regulator in numerous developmental programs, but has also been shown to be an important player in the biology of tumorigenesis. In melanoma, BRN2 has been identified as one of the key regulators of the acquisition of invasive behavior in the phenotype switch model of progression.

As a mediator of the phenotype switch of melanoma cells, it coordinates the transition to a de-differentiated, slowly cycling and highly motile cell type. Its inverse expression relationship to MITF is thought to mediate tumor progression and metastasis in this model (Cook AL et al. 2008). Epigenetic switching mechanisms in melanoma cells driven by BRN2 expression may play a role in triggering melanoma cell invasion (Fane ME et al. 2019). Thus, BRN2 mRNA expression is significantly higher in human melanoma cell lines than in melanocytes. Melanoma cells in which BRN2 expression had been inhibited by antisense RNA lose the ability to form tumors in immunodeficient mice. It can also be shown that there is a negative correlation between the degree of differentiation of melanocytes and BRN2 expression.

The promoter of BRN2 can also be activated via the MAP kinase (MAP = Mitogen Activated Protein) signal transduction pathway. This signal transduction pathway, which plays an important role in the control of growth signals, cell survival and cell invasion, is often activated in malignant melanoma by mutations in the BRAF gene. In melanoma cells with activated BRAF, BRN2 leads to increased cell proliferation. The BRN2 promoter is also a target for the WNT/β-catenin signal transduction pathway (Goodall et al., 2004b). This signaling pathway plays an important role in melanocyte development. Its activation in melanoma cells appears to be associated with a metastatic phenotype with increased cell motility. In melanoma cells in which BRN2 expression was controlled by beta-catenin, BRN2 led to increased cell proliferation.

1. Cook AL et al (2005). Co-expression of SOX9 and SOX10 during melanocytic differentiation in vitro. Exp. Cell Res 308: 222-235.
2. Cook AL et al. (2008) POU domain transcription factors: BRN2 as a regulator of melanocytic growth and tumorigenesis. Pigment Cell Melanoma Res 21:611-626.
3. Ding C et al. (2021) Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia. Mol Psychiatry 26:3444-3460.
4. Fane ME et al. (2019) BRN2, a POUerful driver of melanoma phenotype switching and metastasis. Pigment Cell Melanoma Res 32:9-24.
5. Goodall J et al. (2008) Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphthalmia-associated transcription factor-negative melanoma cells. Cancer Res 68: 7788-7794.
6. Huang YT et al. (2005) The neuronal POU transcription factor Brn-2 interacts with Jab1, a gene involved in the onset of neurodegenerative diseases. Neurosci. Lett 382: 175-178.
7. Jin S et al. (2001) Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage. Oncogene 20: 2683-2690.
8. Lee SA et al. (2005) Expression of the Brn-3b transcription factor correlates with expression of HSP-27 in breast cancer biopsies and is required for maximal activation of the HSP-27 promoter. Cancer Res 65; 3072-3080.
9. Lefort K et al. (2001). The specific activation of gadd45 following UVB radiation requires the POU family gene product N-oct3 in human melanoma cells. Oncogene 20: 7375-7385.
10. Vance KW et al. (2004) The transcription network regulating melanocyte development and melanoma. Pigment Cell Res 17: 318-325.
11. Wang Z et al. (2022) Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer. iScience 25:104576.