Abstract
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, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.
Highlights
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
BRN2 has been implicated in melanoma invasiveness, and its expression is highly regulated, whether and how it may contribute to melanoma initiation or incidence is not understood
It appears that 28% (5 out of 18) or 22% (4 out of 18) of melanomas presented either a mono-allelic loss or a gain of BRN2 respectively compared to nevi (Supplementary Fig. 1D)
Summary
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. Activation of BRAF or NRAS is insufficient to promote melanoma initiation without senescence bypass mediated by additional founder mutations or expression changes of several genes including p16INK4A, CTNNB1, PTEN, or MDM43–7. The activation of BRN2 expression in a specific subset of melanoma cells in response to all three major signaling pathways (MAPK, PI3K/ PTEN, and β-catenin) linked to melanoma initiation (early proliferation and bypass/escape senescence) and progression (including late proliferation and metastatic dissemmination) suggests that Brn[2] is likely to have a critical role in disease progression[26]. We show that BRN2 acts as a tumor suppressor during melanoma initiation and progression in a BRAF-PTEN context since BRN2 and MITF regulate positively and negatively the transcription of PTEN, respectively
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