Cell death & disease · 2025
SETDB1 is critically required for uveal melanoma growth and represents a promising therapeutic target.
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Krossa Imène, Pisibon Céline, Cheli Yann, Bille Karine, Dalmasso Mélanie, Hamadat Sabah, Husser Chrystel, Irondelle Marie, Cherfils-Vicini Julien, Soysouvanh Frédéric, Nahon-Esteve Sacha, Martel Arnaud, Lassalle Sandra, Caujolle Jean-Pierre, Maschi Célia, Baillif Stéphanie, Hasson Dan, Carcamo Saul, Aplin Andrew E, Davidson Irwin, Bernstein Emily, Naim Valeria, Ballotti Robert, Bertolotto Corine, Strub Thomas
Аннотация
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.