2. Academic Validation
  3. SETDB1 is critically required for uveal melanoma growth and represents a promising therapeutic target

SETDB1 is critically required for uveal melanoma growth and represents a promising therapeutic target

  • Cell Death Dis. 2025 Oct 24;16(1):754. doi: 10.1038/s41419-025-08084-z.
Imène Krossa 1 2,  Céline Pisibon 1 2,  Yann Cheli 1 2,  Karine Bille 1 2,  Mélanie Dalmasso 1 2,  Sabah Hamadat 3 4,  Chrystel Husser 1 2,  Marie Irondelle 1,  Julien Cherfils-Vicini 1 5,  Frédéric Soysouvanh 1 2,  Sacha Nahon-Esteve 1 2 6,  Arnaud Martel 1 2 6,  Sandra Lassalle 1 2 7,  Jean-Pierre Caujolle 1 2 6,  Célia Maschi 1 2 6,  Stéphanie Baillif 1 2 6,  Dan Hasson 8,  Saul Carcamo 8,  Andrew E Aplin 9 10,  Irwin Davidson 11,  Emily Bernstein 12,  Valeria Naim 3,  Robert Ballotti # 1 2,  Corine Bertolotto # 13 14,  Thomas Strub # 15 16
Affiliations

Affiliations

  • 1 University Côte d'Azur, Nice, France.
  • 2 Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2025 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
  • 3 CNRS UMR9019 Genome Integrity and Cancers, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 4 Inovarion, Paris, 75005, France.
  • 5 Centre National de la Recherche Scientifique (CNRS) UMR7284, Inserm U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, 06107, France.
  • 6 Department of Ophthalmology, Centre Hospitalier Universitaire of Nice, Nice, France.
  • 7 Laboratory of Clinical and Experimental Pathology (LPCE), Biobank BB-0033-00025, Nice, France.
  • 8 Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 9 Department of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 10 Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 11 IGBMC, CNRS UMR7104, INSERM U1258, Université de Strasbourg, Illkirch, France.
  • 12 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • 13 University Côte d'Azur, Nice, France. Corine.Bertolotto@univ-cotedazur.fr.
  • 14 Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2025 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, Nice, France. Corine.Bertolotto@univ-cotedazur.fr.
  • 15 University Côte d'Azur, Nice, France. thomas.strub@univ-cotedazur.fr.
  • 16 Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2025 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, Nice, France. thomas.strub@univ-cotedazur.fr.
  • # Contributed equally.
PMID: 41136387 DOI: 10.1038/s41419-025-08084-z
Abstract

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.

Figures
Products