George Joun, Emma G. Kempe, Brianna Chen, Jayden Sterling, Ramzi H. Abbassi, Dana Friess, Matthew Singleton, Chandra Choudhury, Oana C. Marian, Willem 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
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.