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
  • 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. [email protected].
  • 14. Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2025 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, Nice, France. [email protected].
  • 15. University Côte d'Azur, Nice, France. [email protected].
  • 16. Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2025 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, Nice, France. [email protected].
  • # Contributed equally.
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.

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