BRN2 is a non-canonical melanoma tumor-suppressor

Michael Hamm (1) , Pierre Sohier (1) , Valérie Petit (1) , Jérémy H Raymond (1) , Véronique Delmas (1) , Madeleine Le Coz (1) , Franck Gesbert (1) , Colin Kenny (2) , Zackie Aktary (1) , Marie Pouteaux (1) , Florian Rambow (1) , Alain Sarasin (3) , Nisamanee Charoenchon (1, 4) , Alfonso Bellacosa (5) , Luis Sanchez-Del-Campo (6) , Laura Mosteo (6) , Martin Lauss (7) , Dies Meijer (8) , Eirikur Steingrimsson (9) , Göran B Jönsson (7) , Robert A Cornell (10) , Irwin Davidson (10, 11) , Colin R Goding (6) , Lionel Larue (1)

1 Signalisation, radiobiologie et cancer
2 Carver College of Medicine [Iowa City]
3 UMR 8200 - Stabilité Génétique et Oncogenèse
4 Mahidol University [Bangkok]
5 Fox Chase Cancer Center
6 University of Oxford
7 Skane University Hospital [Lund]
8 Edin. - University of Edinburgh
9 University of Iceland [Reykjavik]
10 Carver College of Medicine, University of Iowa
11 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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 Braf V600E Pten F/+ 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.

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Michael Hamm, Pierre Sohier, Valérie Petit, Jérémy H Raymond, Véronique Delmas, et al.. BRN2 is a non-canonical melanoma tumor-suppressor. Nature Communications, 2021, 12 (1), pp.3707. ⟨10.1038/s41467-021-23973-5⟩. ⟨hal-03437816v2⟩