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<p>Chemotherapy often kills a large fraction of cancer cells but leaves behind a small population of drug-tolerant persister cells. These persister cells survive drug treatments through reversible, non-genetic mechanisms and cause tumour recurrence upon cessation of therapy. Here, we report a drug tolerance mechanism regulated by the germ-cell-specific H3K4 methyltransferase PRDM9. Through histone proteomic, transcriptomic, lipidomic, and ChIP-sequencing studies combined with CRISPR knockout and phenotypic drug screen, we identify that chemotherapy-induced PRDM9 upregulation promotes metabolic rewiring in glioblastoma stem cells, leading to chemotherapy tolerance. Mechanistically, PRDM9-dependent H3K4me3 at cholesterol biosynthesis genes enhances cholesterol biosynthesis, which persister cells rely on to maintain homeostasis under chemotherapy-induced oxidative stress and lipid peroxidation. PRDM9 inhibition, combined with chemotherapy, results in strong anti-cancer efficacy in preclinical glioblastoma models, significantly enhancing the magnitude and duration of the antitumor response by eliminating persisters. These findings demonstrate a role of PRDM9 in promoting metabolic reprogramming that enables the survival of drug-tolerant persister cells.</p>

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Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

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  • George L. Joun,
  • Emma G. Kempe,
  • Brianna Chen,
  • Jayden R. Sterling,
  • Ramzi H. Abbassi,
  • Dana Friess,
  • Matthew Singleton,
  • Chandra Choudhury,
  • Oana C. Marian,
  • W. Daniel du Preez,
  • Ariadna Recasens,
  • Teleri Clark,
  • Tian Y. Du,
  • Jason K. K. Low,
  • Hani Kim,
  • Pengyi Yang,
  • Jasmine Khor,
  • Monira Hoque,
  • Dinesh C. Indurthi,
  • Mani Kuchibhotla,
  • Ranjith Palanisamy,
  • William T. Jorgensen,
  • Andrew P. Montgomery,
  • Jennifer R. Baker,
  • Sarah L. Higginbottom,
  • Eva Tomaskovic-Crook,
  • Jeremy M. Crook,
  • Lipin Loo,
  • Bryan W. Day,
  • G. Gregory Neely,
  • Ernesto Guccione,
  • Terrance G. Johns,
  • Michael Kassiou,
  • Yuchen Feng,
  • Lachlan Harris,
  • Anthony S. Don,
  • Lenka Munoz

摘要

Chemotherapy often kills a large fraction of cancer cells but leaves behind a small population of drug-tolerant persister cells. These persister cells survive drug treatments through reversible, non-genetic mechanisms and cause tumour recurrence upon cessation of therapy. Here, we report a drug tolerance mechanism regulated by the germ-cell-specific H3K4 methyltransferase PRDM9. Through histone proteomic, transcriptomic, lipidomic, and ChIP-sequencing studies combined with CRISPR knockout and phenotypic drug screen, we identify that chemotherapy-induced PRDM9 upregulation promotes metabolic rewiring in glioblastoma stem cells, leading to chemotherapy tolerance. Mechanistically, PRDM9-dependent H3K4me3 at cholesterol biosynthesis genes enhances cholesterol biosynthesis, which persister cells rely on to maintain homeostasis under chemotherapy-induced oxidative stress and lipid peroxidation. PRDM9 inhibition, combined with chemotherapy, results in strong anti-cancer efficacy in preclinical glioblastoma models, significantly enhancing the magnitude and duration of the antitumor response by eliminating persisters. These findings demonstrate a role of PRDM9 in promoting metabolic reprogramming that enables the survival of drug-tolerant persister cells.