BRN2 is a non-canonical melanoma tumor-suppressor

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 () and Lionel Larue ()
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Michael Hamm: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Pierre Sohier: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Valérie Petit: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Jérémy H. Raymond: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Véronique Delmas: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Madeleine Le Coz: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Franck Gesbert: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Colin Kenny: University of Iowa
Zackie Aktary: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Marie Pouteaux: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Florian Rambow: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Alain Sarasin: Université Paris-Sud
Nisamanee Charoenchon: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes
Alfonso Bellacosa: Fox Chase Cancer Center
Luis Sanchez-del-Campo: University of Oxford, Headington
Laura Mosteo: University of Oxford, Headington
Martin Lauss: Lund University and Skåne University Hospital
Dies Meijer: University of Edinburgh
Eirikur Steingrimsson: University of Iceland
Göran B. Jönsson: Lund University and Skåne University Hospital
Robert A. Cornell: University of Iowa
Irwin Davidson: University of Iowa
Colin R. Goding: University of Oxford, Headington
Lionel Larue: Institut Curie, Université PSL, CNRS UMR3347, Inserm U1021, Normal and Pathological Development of Melanocytes

Nature Communications, 2021, vol. 12, issue 1, 1-16

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, in a BrafV600E PtenF/+ 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.

Date: 2021
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DOI: 10.1038/s41467-021-23973-5

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