Brn-2 Represses Microphthalmia-Associated Transcription Factor Expression and Marks a Distinct Subpopulation of Microphthalmia-Associated Transcription Factor–Negative Melanoma Cells

Abstract

The origin of tumor heterogeneity is poorly understood, yet it represents a major barrier to effective therapy. In melanoma and in melanocyte development, the microphthalmia-associated transcription factor (Mitf) controls survival, differentiation, proliferation, and migration/metastasis. The Brn-2 (N-Oct-3, POU3F2) transcription factor also regulates melanoma proliferation and is up-regulated by BRAF and B-catenin, two key melanoma-associated signaling molecules. Here, we show that Brn-2 also regulates invasiveness and directly represses Mitf expression. Remarkably, in melanoma biopsies, Mitf and Brn-2 each mark a distinct subpopulation of melanoma cells, providing a striking illustration of melanoma tumor heterogeneity with implications for melanoma therapy.

Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

“…Interestingly, BRN-2 (POU3F2), which belongs with Oct4 (POU5F1) to the POU domain transcription factor family, functions at the cross road between ERK and WNT pathways. BRN-2 identifies in some melanoma, a population of Mitf negative cells with increased invasive properties (Goodall et al, 2008). Intravital imaging study revealed a reversible switching between poorly differentiated, BRN-2-high and highly pigmented BRN-2-low melanoma cells (Pinner et al, 2009).…”

[6]-Shogaol inhibits melanogenesis in B16 mouse melanoma cells through activation of the ERK pathway

“…This pathway is also involved in the regulation of melanin synthesis. It has been reported that activation of MEK/ERK leads to phosphorylation of MITF at serine 73, resulting in its degradation [28,38] . The PI3K⁄Akt pathway plays an important role in cell growth regulation and apoptosis inhibition [39,40] .…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…In this context, mTOR inhibition has also been shown to suppress the outgrowth of clones with resistance to MAPK inhibition 126 . Finally, in those melanomas in which MITF expression is not restored 132 , many receptor tyrosine kinases can be upregulated and contribute to the resistant phenotype 133,134 (FIG. 4a).…”