Poster Presentation 38th Lorne Cancer Conference 2026

PRDM9-Mediated H3K4me3 Drives Cholesterol Metabolic Gene Expression and Chemotherapy Tolerance in Glioblastoma (#168)

George L Joun 1 2 , Emma G Kempe 1 2 , Tian Y Du 1 2 3 , Oana C Marian 1 2 , Hani Kim 2 4 , Pengyi Yang 2 4 , Gregory Neely 2 3 , Anthony S Don 1 2 , Lenka Munoz 1 2
  1. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
  2. Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
  3. School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, NSW, Australia
  4. School of Mathematics and Statistics, Faculty of Science, The University of Sydney, Camperdown, NSW, Australia

PR/SET Domain 9 (PRDM9) is normally restricted to gametes, where it deposits H3K4me3 marks at sites of meiotic recombination. We discovered that PRDM9 is aberrantly re-expressed in glioblastoma, where it maintains drug tolerance to microtubule-targeting agent (MTA) chemotherapy. Using H3K4me3 ChIP-seq in glioblastoma stem cells, PRDM9 knockout models, and patient tumours, we confirmed PRDM9 activity and found that its inhibition causes widespread loss of promoter H3K4me3 marks. RNA-sequencing revealed that cholesterol biosynthesis genes are especially sensitive to PRDM9 inhibition, with H3K4me3 enrichment at promoters of key genes (e.g., DHCR24, DHCR7) strongly correlating with their transcript levels in tumours. PRDM9 inhibition or knockout lowered cholesterol and precursor metabolites, and supplementation with cholesterol restored drug tolerance in persisters. Mechanistically, PRDM9 inhibition increased lipid peroxidation in persisters, while N-acetylcysteine supplementation rescued persister survival. Together, these findings establish PRDM9-mediated H3K4me3 as a crucial regulator of cholesterol metabolism that supports glioblastoma persister survival during chemotherapy.