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

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 prov

SUBMITTER: Krossa I 

PROVIDER: S-EPMC12552495 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature