KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage.

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.

Description

Acknowledgements: We thank members of our laboratories for their critical reading of this paper and useful discussions. We thank W. Kaelin (DFCI) and M. Eck (DFCI) for useful discussions on KDM4C and the structural biology of GRHL2 and CTSL complex, respectively. We thank the DFCI Molecular Biology Core Facility for its outstanding sequencing service. We thank the N. Danial Lab (DFCI) for technical assistance and training for the seahorse assay. We thank A. Welm (University of Utah) for providing us with PDX samples. We thank the Bioinformatics Core at the Cancer Research UK Cambridge Institute for the analysis of the RIME data. This research was supported by the Department of Defense (W81XWH-14-1-0212 to A.M. and K.P.), the National Cancer Institute (NCI; R35 CA197623 to K.P. and P01CA250959 to K.P. and H.L.) and the Charles A. King Trust Postdoctoral Research Fellowship (to Z.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health/NCI.

Funder: Charles A King Trust

Keywords

Breast Neoplasms, Cathepsin L, Humans, Female, Jumonji Domain-Containing Histone Demethylases, Histones, Animals, Mice, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Transcription Factors, Methylation, Chromatin, Reactive Oxygen Species, Cell Proliferation, Proteolysis, Chromatin Assembly and Disassembly

Journal Title

Nat Genet

Journal ISSN

1061-4036
1546-1718

Volume Title

57

Publisher

Springer Nature

Publisher DOI

https://doi.org/10.1038/s41588-025-02197-z

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (CA197623, CA250959, CA250959)
United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP) (W81XWH-14-1-0212, W81XWH-14-1-0212)
European Molecular Biology Organization (EMBO) (NA)
American Brain Tumor Association (ABTA) (NA)

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