Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma.
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Joun George L, Kempe Emma G, Chen Brianna, Sterling Jayden R, Abbassi Ramzi H, Friess Dana, Singleton Matthew, Choudhury Chandra, Marian Oana C, du Preez W Daniel, Recasens Ariadna, Clark Teleri, Du Tian Y, Low Jason K K, Kim Hani, Yang Pengyi, Khor Jasmine, Hoque Monira, Indurthi Dinesh C, Kuchibhotla Mani, Palanisamy Ranjith, Jorgensen William T, Montgomery Andrew P, Baker Jennifer R, Higginbottom Sarah L, Tomaskovic-Crook Eva, Crook Jeremy M, Loo Lipin, Day Bryan W, Neely G Gregory, Guccione Ernesto, Johns Terrance G, Kassiou Michael, Feng Yuchen, Harris Lachlan, Don Anthony S, Munoz Lenka
Аннотация
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.