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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月24日

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  • Imène Krossa,
  • Céline Pisibon,
  • Yann Cheli,
  • Karine Bille,
  • Mélanie Dalmasso,
  • Sabah Hamadat,
  • Chrystel Husser,
  • Marie Irondelle,
  • Julien Cherfils-Vicini,
  • Frédéric Soysouvanh,
  • Sacha Nahon-Esteve,
  • Arnaud Martel,
  • Sandra Lassalle,
  • Jean-Pierre Caujolle,
  • Célia Maschi,
  • Stéphanie Baillif,
  • Dan Hasson,
  • Saul Carcamo,
  • Andrew E. Aplin,
  • Irwin Davidson,
  • Emily Bernstein,
  • Valeria Naim,
  • Robert Ballotti,
  • Corine Bertolotto,
  • Thomas Strub

摘要

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.