KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage.
- Abstract:
- Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in KDM4C-amplified basal breast cancers, where KDM4C inhibition reshapes chromatin and transcriptomic landscapes without substantial alterations of its canonical substrates, trimethylated histone H3 lysine 9 (H3K9me3) and lysine 36 (H3K36me3). Rather, KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL), resulting in decreased glutamate-cysteine ligase expression and increased reactive oxygen species. CTSL is recruited to the chromatin by the grainyhead-like 2 (GRHL2) transcription factor that is methylated at lysine 453 following KDM4C inhibition, triggering CTSL histone clipping activity. Deletion of CTSL rescued KDM4-loss-mediated tumor suppression. Our study reveals a function for KDM4C that connects cellular redox regulation and chromatin remodeling.
- Authors:
- Z Li, G Peluffo, LE Stevens, X Qiu, M Seehawer, A Tawawalla, X-Y Huang, SB Egri, S Raval, M McFadden, CS D'Santos, E Papachristou, NL Kingston, J Nishida, KE Evans, J-H Seo, K Clement, D Temko, M Ekram, R Li, MG Rees, MM Ronan, JA Roth, A Simeonov, SC Kales, G Rai, M Lal-Nag, DJ Maloney, A Jadhav, F Michor, A Meissner, JM Balko, JS Carroll, ML Freedman, JD Jaffe, M Papanastasiou, HW Long, K Polyak
- Journal:
- Nat Genet
- Citation info:
- 57(6):1463-1477
- Publication date:
- 1st Jun 2025
- Full text
- DOI