Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma
Abstract
Abstract 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.
Article Details
Authors (37)
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