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

Zheqi Li; Guillermo Peluffo; Laura E Stevens; Xintao Qiu; Marco Seehawer; Amatullah Tawawalla; Xiao-Yun Huang; Shawn B Egri; Shaunak Raval; Maeve McFadden; Clive S D'Santos; Eva Papachristou; Natalie L Kingston; Jun Nishida; Kyle E Evans; Ji-Heui Seo; Kendell Clement; Daniel Temko; Muhammad Ekram; Rong Li; Matthew G Rees; Melissa M Ronan; Jennifer A Roth; Anton Simeonov; Stephen C Kales; Ganesha Rai; Madhu Lal-Nag; David J Maloney; Ajit Jadhav; Franziska Michor; Alex Meissner; Justin M Balko; Jason S Carroll; Matthew L Freedman; Jacob D Jaffe; Malvina Papanastasiou; Henry W Long; Kornelia Polyak

doi:10.1038/s41588-025-02197-z

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

Nat Genet. 2025 Jun;57(6):1463-1477. doi: 10.1038/s41588-025-02197-z. Epub 2025 Jun 2.

Authors

Zheqi Li^#^{1

2

3}, Guillermo Peluffo^#^{1

2

3}, Laura E Stevens^{1

2

3}, Xintao Qiu⁴, Marco Seehawer^{1

2

3}, Amatullah Tawawalla¹, Xiao-Yun Huang¹, Shawn B Egri⁵, Shaunak Raval⁵, Maeve McFadden⁵, Clive S D'Santos⁶, Eva Papachristou⁶, Natalie L Kingston¹, Jun Nishida^{1

2

3}, Kyle E Evans¹, Ji-Heui Seo^{1

2

3}, Kendell Clement⁷, Daniel Temko^{7

8

9}, Muhammad Ekram^{1

2

3}, Rong Li⁴, Matthew G Rees⁵, Melissa M Ronan⁵, Jennifer A Roth⁵, Anton Simeonov¹⁰, Stephen C Kales¹⁰, Ganesha Rai¹⁰, Madhu Lal-Nag¹⁰, David J Maloney¹⁰, Ajit Jadhav¹⁰, Franziska Michor^{5

7

8

9}, Alex Meissner^{5

7}, Justin M Balko¹¹, Jason S Carroll⁶, Matthew L Freedman^{1

2

3

4

5}, Jacob D Jaffe⁵, Malvina Papanastasiou⁵, Henry W Long⁴, Kornelia Polyak^{12

13

14

15

16}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
⁶ Cambridge Research Institute, University of Cambridge, Cambridge, UK.
⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁸ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁹ Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ National Center for Advancing Translational Sciences, Bethesda, MD, USA.
¹¹ Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
¹³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
¹⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
¹⁵ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.
¹⁶ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. kornelia_polyak@dfci.harvard.edu.

^# Contributed equally.

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.

MeSH terms

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

Substances

Cathepsin L
Jumonji Domain-Containing Histone Demethylases
Histones
KDM4C protein, human
Transcription Factors
Chromatin
Reactive Oxygen Species

Abstract

MeSH terms

Substances

Grants and funding