While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression.

中文翻译：

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BRN2是一种非规范性黑色素瘤肿瘤抑制因子

虽然已经确定了黑素瘤引发的主要驱动因素，包括NRAS / BRAF的激活和PTEN或CDKN2A的丧失，但人们对关键转录因子在响应信号转导失调后施加转录状态改变的作用尚不十分了解。POU域转录因子BRN2是黑色素瘤侵袭的关键调节因子，但其在黑色素瘤引发中的作用仍然未知。在这里，我们显示BRN2单倍体功能不足足以促进黑色素瘤的起始和转移，充当非规范性的肿瘤抑制因子。从机理上讲，BRN2直接调节PTEN表达和PI3K信号传导，从而驱动肿瘤的发生和发展。我们的研究结果共同表明，一个BRN2等位基因的体细胞缺失会引发黑色素瘤的发生和发展。