BRN2, a POUerful driver of melanoma phenotype switching and metastasis

Abstract

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.

A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITFhigh/AXLlow melanoma

“…The situation was, however, different with BRN2, whose expression did not significantly correlate with AXL (Figure c and Supporting Information Figure D). Thus, although BRN2 has been established as driver of an invasive phenotype classified by low MITF expression (Arozarena et al, ; Fane, Chhabra, Smith, & Sturm, ; Goodall et al, ), its expression pattern does not align with the marker for the well‐characterized AXL high /MITF low phenotype.…”

BRN 2 Invade

“…While MITF represses BRN2 expression (via miR-211), BRN2-directly represses MITF transcription (Goodall et al, 2008), constituting a positive feedback loop that underlies the mutually exclusive expression observed in human melanoma. Consistent with this, high MITF levels are known to promote a proliferative state, whereas low MITF levels are associated with an invasive, slow-cycling phenotype (Fane et al, 2018). Because low MITF expression is thought to impair cell proliferation, it is possible that MITF downregulation at the G1–S checkpoint is mediated by the loss of CDKN2A and upregulation of BRN2, changes that underlie switching between the proliferative and the invasive phenotypes.…”

“…They also identified a similar inverse relationship between p16 INK4A activity and invasive/metastatic potential in vivo by using isogenic melanoma cell lines that differed in their ability to form distant metastases. Mechanistically, Zeng et al demonstrated that E2F1 promotes transcriptional activation of the POU domain transcription factor BRN2, which has been implicated in melanocytic development and differentiation in culture (Fane et al, 2018) and melanoma metastasis in vivo (Pinner et al, 2009). Thus, the study by Zeng et al extends the established link between p16 INK4A , pRb, and E2F1 to identify a novel association with BRN2 and the invasive capacity of melanoma.…”

“…A number of studies have pointed to a functional separation between the proliferative and invasive capabilities of melanoma (Fane et al, 2018), suggesting they may be mutually exclusive phenotypes. Therefore, it will be important to determine whether the effects of p16 INK4A on proliferation and invasion can also be distinguished mechanistically.…”

“…BRN2 is expressed in a mutually exclusive fashion with MITF (microphthalmia-associated transcription factor), a master regulator of melanocyte biogenesis with proposed roles in melanomagenesis (Fane et al, 2018). While MITF represses BRN2 expression (via miR-211), BRN2-directly represses MITF transcription (Goodall et al, 2008), constituting a positive feedback loop that underlies the mutually exclusive expression observed in human melanoma.…”