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.
- 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.
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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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer