Fiche publication
Date publication
octobre 2025
Journal
Cell death & disease
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIDSON Irwin
Tous les auteurs :
Krossa I, Pisibon C, Cheli Y, Bille K, Dalmasso M, Hamadat S, Husser C, Irondelle M, Cherfils-Vicini J, Soysouvanh F, Nahon-Esteve S, Martel A, Lassalle S, Caujolle JP, Maschi C, Baillif S, Hasson D, Carcamo S, Aplin AE, Davidson I, Bernstein E, Naim V, Ballotti R, Bertolotto C, Strub T
Lien Pubmed
Résumé
Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs tumor growth in vivo. Therefore, we not only provide evidence that SETDB1 plays a critical role in metastatic uveal melanoma cell growth, but we also identify SETDB1 as a novel relevant therapeutic target for the treatment of metastatic uveal melanoma.
Mots clés
Uveal Neoplasms, pathology, Melanoma, pathology, Humans, Uveal Melanoma, Histone-Lysine N-Methyltransferase, metabolism, Cell Proliferation, Animals, Cell Line, Tumor, Mice, Cell Cycle Proteins, metabolism, Gene Expression Regulation, Neoplastic, Mice, Nude, DNA Damage
Référence
Cell Death Dis. 2025 10 24;16(1):754
