Browsing by Author "Læknadeild Háskóla Íslands"

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    BRN2 is a non-canonical melanoma tumor-suppressor
    (2021-12-01) Michael Hamm; Pierre Sohier; Valérie Petit; Jérémy H. Raymond; Véronique Delmas; Madeleine Le Coz; Franck Gesbert; Colin Kenny; Zackie Aktary; Marie Pouteaux; Florian Rambow; Alain Sarasin; Nisamanee Charoenchon; Alfonso Bellacosa; Luis Sanchez-del-Campo; Laura Mosteo; Martin Lauss; Dies Meijer; Eirikur Steingrimsson; Göran B. Jönsson; Robert A. Cornell; Irwin Davidson; Colin R. Goding; Lionel Larue; Université PSL; Universite Paris-Saclay; Læknadeild Háskóla Íslands; Institut de Cancerologie Gustave Roussy; The University of Edinburgh; Skånes universitetssjukhus; Mahidol University; University of Iowa Carver College of Medicine; Fox Chase Cancer Center; Nuffield Department of Medicine; CNRS Centre National de la Recherche Scientifique; Equipe Labellisée Ligue Contre le Cancer
    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.