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.

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.

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase* / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Melanoma* / drug therapy
  • Melanoma* / enzymology
  • Melanoma* / genetics
  • Melanoma* / metabolism
  • Melanoma* / pathology
  • Mice
  • Mice, Nude
  • Uveal Melanoma
  • Uveal Neoplasms* / drug therapy
  • Uveal Neoplasms* / enzymology
  • Uveal Neoplasms* / genetics
  • Uveal Neoplasms* / metabolism
  • Uveal Neoplasms* / pathology

Substances

  • SETDB1 protein, human
  • Histone-Lysine N-Methyltransferase
  • Cell Cycle Proteins