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BRN2 is a non-canonical melanoma tumor-suppressor

BRN2 is a non-canonical melanoma tumor-suppressor

Title: BRN2 is a non-canonical melanoma tumor-suppressor
Author: Hamm, Michael
Sohier, Pierre
Petit, Valérie
Raymond, Jérémy H.
Delmas, Véronique
Le Coz, Madeleine
Gesbert, Franck
Kenny, Colin
Aktary, Zackie
Pouteaux, Marie
... 14 more authors Show all authors
Date: 2021-06-17
Language: English
Scope: 2013565
Department: Faculty of Medicine
Series: Nature Communications; 12(1)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-23973-5
Subject: Erfðafræði; Húðkrabbamein; Frumur; Cell proliferation/genetics; Genes, tumor suppressor; Gene Expression Regulation, Neoplastic/genetics; Skin Neoplasms/metabolism; Immunohistochemistry; Humans; Phosphatidylinositol 3-Kinases/metabolism; Proto-Oncogene Proteins B-raf/genetics; DNA Copy Number Variations; Gene Knockdown Techniques; Chromatin Immunoprecipitation; Microarray Analysis; Melanoma/genetics; Cell Proliferation/genetics; Genes, Tumor Suppressor; Skin Neoplasms/genetics; POU Domain Factors/genetics; Mice, Inbred C57BL; Mice, Transgenic; Disease Progression; Haploinsufficiency; PTEN Phosphohydrolase/genetics; Animals; Homeodomain Proteins/genetics; Cell Line, Tumor; Mice; RNA, Small Interfering; Microphthalmia-Associated Transcription Factor/metabolism; Mutation; Carcinogenesis/genetics; Cohort Studies; General Physics and Astronomy; General Chemistry; General Biochemistry,Genetics and Molecular Biology
URI: https://hdl.handle.net/20.500.11815/2910

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Hamm , M , Sohier , P , Petit , V , Raymond , J H , 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 , Steingrímsson , E , Jönsson , G B , Cornell , R A , Davidson , I , Goding , C R & Larue , L 2021 , ' BRN2 is a non-canonical melanoma tumor-suppressor ' , Nature Communications , vol. 12 , no. 1 , 3707 , pp. 3707 . https://doi.org/10.1038/s41467-021-23973-5


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.


Publisher Copyright: © 2021, The Author(s).

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