Evidence map›Paper›PMID 40457074›Full record

ArticleNature genetics2025

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 and 28 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Review
  2. Review
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  4. Article
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  6. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

38 authors.

Zheqi Li *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-1213-640X
Guillermo Peluffo *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Laura E StevensDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Xintao QiuCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8560-7017
Marco SeehawerDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0440-6967
Amatullah TawawallaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Xiao-Yun HuangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Shawn B EgriThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
Shaunak RavalThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
Maeve McFaddenThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0009-0003-7412-8496
Clive S D'SantosCambridge Research Institute, University of Cambridge, Cambridge, UK.
Eva PapachristouCambridge Research Institute, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-5835-2055
Natalie L KingstonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0122-907X
Jun NishidaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5098-9361
Kyle E EvansDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ji-Heui SeoDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Kendell ClementDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-3808-0811
Daniel TemkoDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-0165-292X
Muhammad EkramDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5555-6872
Rong LiCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0009-0000-1046-9580
Matthew G ReesThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2987-7581
Melissa M RonanThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4269-1404
Jennifer A RothThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-5117-5586
Anton SimeonovNational Center for Advancing Translational Sciences, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-4523-9977
Stephen C KalesNational Center for Advancing Translational Sciences, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-8702-5766
Ganesha RaiNational Center for Advancing Translational Sciences, Bethesda, MD, USA.
Madhu Lal-NagNational Center for Advancing Translational Sciences, Bethesda, MD, USA.
David J MaloneyNational Center for Advancing Translational Sciences, Bethesda, MD, USA.
Ajit JadhavNational Center for Advancing Translational Sciences, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-7955-1451
Franziska MichorThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4869-8842
Alex MeissnerThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8646-7469
Justin M BalkoVanderbilt University Medical Center, Nashville, TN, USA.ORCID http://orcid.org/0000-0002-4263-5974
Jason S CarrollCambridge Research Institute, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-3643-0080
Matthew L FreedmanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jacob D JaffeThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
Malvina PapanastasiouThe Eli and Edythe L. Broad Institute, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-3378-6612
Henry W LongCenter for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0001-6849-6629
Kornelia PolyakDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu.ORCID http://orcid.org/0000-0002-5964-0382

Funding

Targeting intratumor heterogeneity in breast cancerR35CA197623 · NCI · DANA-FARBER CANCER INST · PI KORNELIA POLYAK · 2015 to 2026
$12.4M
Tissue and Pathology CoreP01CA250959 · NCI · DANA-FARBER CANCER INST · PI POLYAK, KORNELIA · 2020 to 2024
$8.6M
Cancer Chemical Biology and Metabolism Training ProgramT32CA236754 · NCI · DANA-FARBER CANCER INST · PI Nika N Danial, THOMAS M ROBERTS · 2019 to 2026
$2.6M
American Brain Tumor Association (ABTA) NAEuropean Molecular Biology Organization (EMBO) NANCI NIH HHS P01 CA250959NCI NIH HHS R35 CA197623NCI NIH HHS T32 CA236754United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP) W81XWH-14-1-0212U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA197623U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA250959
6 · The paper itself

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.

Indexed as

Breast NeoplasmsCathepsin LHistonesJumonji Domain-Containing Histone DemethylasesAnimalsCell Line, TumorCell ProliferationChromatinChromatin Assembly and DisassemblyFemaleGene Expression Regulation, NeoplasticHumansMethylationMiceProteolysisReactive Oxygen SpeciesCathepsin LChromatinHistonesJumonji Domain-Containing Histone DemethylasesKDM4C protein, humanReactive Oxygen SpeciesTranscription Factors

Identifiers

PMID40457074
PMCPMC12165855

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.