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    • The nuclear factor one NF family consists

    2018-11-07

    The nuclear factor one (NF1) family consists of four site-specific transcription factors (NfiA, NfiB, NfiC, and NfiX) that play a large role in the development of a number of organs systems such as the lung and contact us (Grunder et al., 2002; Harris et al., 2015; Hsu et al., 2011; Steele-Perkins et al., 2005), and is upregulated in many epithelial type cancers (Dooley et al., 2011; Moon et al., 2011). While the expression of NFIB has not been reported in melanocytic cells, recent findings have demonstrated that NFIB governs epithelial-melanocyte stem cell behavior in a shared niche (Chang et al., 2013). Interestingly BRN2 has been proposed to maintain a less differentiated, stem cell-like phenotype in melanoblasts and a subset of melanoma cells (Cook et al., 2003; Cook and Sturm, 2008; Goodall et al., 2008). Accordingly, we chose to examine the expression and function of NFIB in the context of BRN2 function in primary melanocytic cells and melanoma cells to determine if this transcription factor plays a role in BRN2 mediated phenotype switching.
    Materials and Methods
    Results
    Discussion Cellular heterogeneity has been linked to progression and therapeutic resistance in numerous cancer types (Marusyk et al., 2012). In melanoma, heterogeneous expression of the BRN2 and MITF transcription factors has been proposed to constitute a crucial switching mechanism between invasive and proliferative phenotypes (Goodall et al., 2008; Hoek et al., 2008; Hoek and Goding, 2010; Pinner et al., 2009; Quintana et al., 2010; Thurber et al., 2011). MITF has been identified as a crucial oncogene in melanoma, and accumulative evidence supports the hypothesis that its expression acts as a rheostat in controlling cell cycle behavior and migration/invasion (Carreira et al., 2006; Goding, 2011). In the context of phenotype switching, MITF expression has been characterized as a driver of a highly proliferative, less invasive cell state (Hoek et al., 2008; Vandamme and Berx, 2014). Conversely, BRN2 has been implicated in promoting an invasive and less differentiated state that is important in driving tumour progression towards metastasis, however few downstream targets of BRN2 that facilitate this phenotype have been identified (Arozarena et al., 2011; Boyle et al., 2011; Pinner et al., 2009). Moreover, the mechanism that underpins the switch between BRN2/MITF expression and associated phenotypes remains poorly understood. Here we report the regulation of expression of the NFIB transcription factor by BRN2 in melanoma cells, which in turn acts to increase cell migration and potentially invasion through the positive and negative regulation of the epigenetic regulator EZH2 and MITF respectively. The expression and function of NFIB has not previously been explored in melanoma, but has been characterized as an oncogene in various cancers and is frequently amplified in epithelial type cancers (Chang et al., 2013; Dooley et al., 2011; Persson et al., 2009). Interestingly, NFIB activity in the skin has been demonstrated to be a key regulator of stem cell behavior in melanocytic stem cell niches (Chang et al., 2013). In this context, it has been shown that knockout of NFIB within this shared niche results in premature differentiation and proliferation of melanocytic stem cells. Similarly, BRN2 expression has been shown to maintain an undifferentiated melanoblast like cell phenotype during melanocyte development (Cook et al., 2003, 2005). Using a cultured human primary MB cell system, we observed high levels of BRN2 and NFIB protein in melanoblast cells that decreased dramatically over the course of differentiation into mature melanocytes. This role for BRN2 in facilitating a less differentiated phenotype has been observed in sub-sets of cells within melanoma tumours that are known to be more invasive (Pinner et al., 2009). The concept that cells undergo a process of de-differentiation to a more stem-cell like phenotype to help enhance metastasis has been well documented in various cancer models (Cheng et al., 1999; Friedmann-Morvinski and Verma, 2014; Sell, 1993). Immunostaining of NFIB within both mouse xenograft and human primary/metastatic melanoma tumours shows clear co-localization with BRN2 expressing populations, indicating that NFIB expression within melanoma tumours is most likely linked with these more undifferentiated and invasive cellular populations previously associated with BRN2 expression (Goodall et al., 2008; Pinner et al., 2009).