SETDB1 is critically required for uveal melanoma growth and represents a promising therapeutic target
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.
Authors
- Stéphanie Baillif
- Sabah Hamadat (ORCID: https://orcid.org/0000-0003-1574-3053)
- Valeria Naim (ORCID: https://orcid.org/0000-0002-2149-8712)
- Céline Pisibon (ORCID: https://orcid.org/0000-0002-9538-761X)
- Karine Bille (ORCID: https://orcid.org/0000-0001-7534-640X)
- Jean‐Pierre Caujolle (ORCID: https://orcid.org/0000-0002-1876-4557)
- Irwin Davidson (ORCID: https://orcid.org/0000-0001-5533-1171)
- Frédéric Soysouvanh (ORCID: https://orcid.org/0000-0001-8197-1615)
- Corine Bertolotto (ORCID: https://orcid.org/0000-0001-6971-7753)
- Emily Bernstein (ORCID: https://orcid.org/0000-0001-6533-8326)
- Andrew E. Aplin (ORCID: https://orcid.org/0000-0002-2734-3244)
- C. Maschi (ORCID: https://orcid.org/0000-0002-9424-1539)
- Robert Ballotti (ORCID: https://orcid.org/0000-0002-7322-4908)
- Sandra Lassalle (ORCID: https://orcid.org/0000-0003-1692-2440)
- Imène Krossa (ORCID: https://orcid.org/0000-0003-0308-2024)
- Chrystel Husser (ORCID: https://orcid.org/0000-0001-8245-672X)
- Thomas Strub (ORCID: https://orcid.org/0000-0001-6252-0181)
- Saul Carcamo (ORCID: https://orcid.org/0000-0002-1510-1045)
- Yann Chéli (ORCID: https://orcid.org/0000-0001-9839-4332)
- Sacha Nahon‐Estève (ORCID: https://orcid.org/0000-0003-2274-0256)
- Mélanie Dalmasso
- Arnaud Martel (ORCID: https://orcid.org/0000-0003-3836-7126)
- Julien Cherfils‐Vicini (ORCID: https://orcid.org/0000-0001-7813-1527)
- Marie Irondelle (ORCID: https://orcid.org/0009-0000-1842-6411)
- Dan Hasson (ORCID: https://orcid.org/0000-0001-7943-1636)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Thomas Jefferson University (US)
- Inserm (FR)
- Université Côte d'Azur (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Scientific Research Institute of Experimental and Clinical Medicine (RU)
- Institut de Biologie Valrose (FR)
- Centre Méditerranéen de Médecine Moléculaire (FR)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- Observatoire de la Côte d’Azur (FR)
- Centre Antoine Lacassagne (FR)
- Neovacs (France) (FR)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Université de Strasbourg (FR)
- Thomas University (US)
- Philadelphia University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1038/s41419-025-08084-z
- Citations
- 1
- Primary Topic
- Ocular Oncology and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- Melanoma Research Alliance
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Fondation de France
- Institut National Du Cancer
- Conseil Régional Provence-Alpes-Côte d'Azur