POU domain transcription factors: BRN2 as a regulator of melanocytic growth and tumourigenesis

Abstract

SummarySeveral parallels between stem cell biology and tumour behaviour have been discovered in recent times. Such commonality is apparent in the unlimited capacity for cell division together with the lack of a differentiated phenotype in embryonic and adult stem cells, traits shared with tumour cells. Differentiation is a tightly regulated process that is mediated by the actions of multiple transcription factor families. The POU domaincontaining family of transcription factors contains multiple mammalian members divided into six classes, which can be expressed broadly or in a cell-specific manner, and which are regulators of cell fate decisions of many different lineages. Target gene regulation can occur via a POU factor acting alone, or in combination with other POU proteins, ubiquitous co-activators or co-repressors, or other lineage restricted transcription factors. Aberrant levels of POU proteins have been found in several malignancies, including melanoma, connecting the otherwise developmentally restricted gene regulatory functions of POU transcription factors to the critical determinants of malignant transformation. Here, we focus on the role of the BRN2 (POU3F2/ N-Oct-3) transcription factor in the melanocytic lineage where it may co-ordinate normal developmental cues that can be re-activated in melanoma. Recent studies have shown BRN2 to be responsive to MAPK pathway activation and to modulate the levels of MITF so as to suppress the differentiated melanocytic phenotype and to enhance tumour metastasis.

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

“…Recently, it has been reported that a combinational transgene of BRN2, ASCL1, and MYT1L (myelin transcription factor 1-like) converts fibroblasts to functional neurons, suggesting the importance of BRN2 in transforming cells to a neural cell lineage. 38 Cook et al 39 reported that BRN2 acts to regulate growth and tumorigenesis in malignant melanomas, which are highly malignant neuroectodermal tumors. Therefore, BRN2 might participate in defining the cellular characteristics of SCLC cells as developing neural cells with high growth ability.…”

The Role of Cellular Differentiation and Cell Fate in Malignant Melanoma

“…Brn-2 is a POU domain transcription factor which regulates melanocytic growth (Cook and Sturm, 2008;Thomson et al, 1995), and in the setting of melanoma, is upregulated by both the MAPK and β-catenin signaling pathways (Goodall et al, 2004a;Goodall et al, 2004b). Increased expression of Brn-2 is a hallmark of invasive melanoma cells, and its activity contributes to this phenotype through a variety of different mechanisms.…”

A POU3F2-MITF-SHC4 Axis in Phenotype Switching of Melanoma Cells

“…The POU family factors have a bipartite DNA binding domain formed by the conserved POU-specific domain (POUs) and the POU homeodomain (POUh) that are joined by a linker region of variable length (Phillips and Luisi, 2000;Ryan and Rosenfeld, 1997). The POUs and POUh domains each comprise a helix-turn-helix structure of which the third helix recognises the DNA and provides sequence specificity (Cook and Sturm, 2008;Klemm et al, 1994). POU3F2 and POU4F1 (BRN3) are involved in development of the central nervous system (Schonemann et al, 1998).…”