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Hamm M , Sohier P , Petit V , Raymond JH , Delmas V , Le Coz M , Gesbert F , Kenny C , Aktary Z , Pouteaux M , Rambow F , Sarasin A , Charoenchon N , Bellacosa A , Sanchez-Del-Campo L , Mosteo L , Lauss M , Meijer D , Steingrimsson E , Jönsson GB , Cornell RA , Davidson I , Goding CR , Larue L
BRN2 is a non-canonical melanoma tumor-suppressor
Nat Commun. 2021 Jun 17;12(1) :3707
PMID: 34140478    PMCID: PMC8211827    URL: https://www.ncbi.nlm.nih.gov/pubmed/34140478
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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 Braf(V600E) Pten(F/+) 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.
2041-1723 Hamm, Michael Sohier, Pierre Orcid: 0000-0002-2341-6848 Petit, Valérie Raymond, Jérémy H Delmas, Véronique Orcid: 0000-0001-7368-3664 Le Coz, Madeleine Gesbert, Franck Kenny, Colin Aktary, Zackie Pouteaux, Marie Rambow, Florian Sarasin, Alain Charoenchon, Nisamanee Bellacosa, Alfonso Sanchez-Del-Campo, Luis Orcid: 0000-0002-9537-7761 Mosteo, Laura Lauss, Martin Meijer, Dies Orcid: 0000-0002-8461-6341 Steingrimsson, Eirikur Jönsson, Göran B Cornell, Robert A Davidson, Irwin Orcid: 0000-0001-5533-1171 Goding, Colin R Orcid: 0000-0002-1614-3909 Larue, Lionel Orcid: 0000-0002-2010-6107 Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2021 Jun 17;12(1):3707. doi: 10.1038/s41467-021-23973-5.