KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage. Nat Genet. 2025 Jun 02.

Citation

Li Z, Peluffo G, Stevens LE, Qiu X, Seehawer M, Tawawalla A, Huang XY, Egri SB, Raval S, McFadden M, D'Santos CS, Papachristou E, Kingston NL, Nishida J, Evans KE, Seo JH, Clement K, Temko D, Ekram M, Li R, Rees MG, Ronan MM, Roth JA, Simeonov A, Kales SC, Rai G, Lal-Nag M, Maloney DJ, Jadhav A, Michor F, Meissner A, Balko JM, Carroll JS, Freedman ML, Jaffe JD, Papanastasiou M, Long HW, Polyak K. 2025. KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage. Nature genetics. 57(6):1463-1477. Pubmed: 40457074 DOI:10.1038/s41588-025-02197-z

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.

Related Faculty

Franziska Michor, Ph.D.

Michor Lab

Franziska Michor uses the tools of theoretical evolutionary biology, applied mathematics, statistics, and computational biology to address important questions in cancer research.