Year: 2021
Type: article
Abstract: 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, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression. SIGNIFICANCE Here, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations ( Braf V600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo . Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.
Source: Nature Communications
Authors: 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
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, Université Paris-Saclay, La Ligue Contre le Cancer, Signalisation, radiobiologie et cancer, Institut Curie, University of Iowa, Université Paris-Sud, Institut Gustave Roussy, Stabilité génétique et oncogenèse, Mahidol University, Fox Chase Cancer Center, University of Oxford, Ludwig Cancer Research, Lund University, Skåne University Hospital, University of Edinburgh, University of Iceland, Institut de génétique et de biologie moléculaire et cellulaire
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: Ludwig Institute for Cancer Research, Infrastructures en Biologie Santé et Agronomie, American Association for Anatomy, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Institut National Du Cancer, Labex CelTisPhyBio, National Institutes of Health, Biotechnology and Biological Sciences Research Council, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1435997383, Paris Sciences et Lettres, G3089088799, G4190806336, G471331628, G4950536974, Regulation of the Melanocyte Lineage by the AP2 Transcription Factor Family, G591834160, Molecular mechanisms of voltage-gated potassium channel clustering in myelinated axons, G628180677, G6358499467, G6759105742, G683439542, G7240651115, G782245399, G8261902651, G844339007, New signaling mechanisms in myelination, G937427620
OpenAlex ID: W3167713534