Michael HammPierre SohierValérie PetitJérémy H. RaymondVéronique DelmasMadeleine Le CozFranck GesbertColin KennyZackie AktaryMarie PouteauxFlorian RambowAlain SarasinNisamanee CharoenchonAlfonso BellacosaLuis Sanchez-del-CampoLaura MosteoMartin LaussDies MeijerEirikur SteingrimssonGöran B. JönssonRobert A. CornellIrwin DavidsonColin R. GodingLionel LarueUniversité PSLUniversite Paris-SaclayLæknadeild Háskóla ÍslandsInstitut de Cancerologie Gustave RoussyThe University of EdinburghSkånes universitetssjukhusMahidol UniversityUniversity of Iowa Carver College of MedicineFox Chase Cancer CenterNuffield Department of MedicineCNRS Centre National de la Recherche ScientifiqueEquipe Labellisée Ligue Contre le Cancer2022-08-042022-08-042021-12-01Nature Communications. Vol.12, No.1 (2021)204117232-s2.0-85108003528https://repository.li.mahidol.ac.th/handle/20.500.14594/75932While 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyChemistryPhysics and AstronomyArticleSCOPUS10.1038/s41467-021-23973-5