[en] KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.
Disciplines :
Oncology
Author, co-author :
Seehawer, Marco ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Li, Zheqi ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Nishida, Jun ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Foidart, Pierre ; Université de Liège - ULiège > Département des sciences cliniques ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Reiter, Andrew H ; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
Rojas-Jimenez, Ernesto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Goyette, Marie-Anne ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Yan, Pengze; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA ; Department of Medicine, Harvard Medical School, Boston, MA, USA
Raval, Shaunak; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
Munoz Gomez, Miguel; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Cejas, Paloma ; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Long, Henry W ; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Papanastasiou, Malvina ; The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu ; Department of Medicine, Harvard Medical School, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu
NIH. NCI - National Institutes of Health. National Cancer Institute EMBO - European Molecular Biology Organization CIFAR - Canadian Institute for Advanced Research
Funding text :
We thank members of our laboratories for critical reading of this manuscript and useful discussions. We thank A. Shilatifard (Northwestern University) for providing KMT2C antibodies and S. Spisak (Dana-Farber Cancer Institute) for providing sgRNA/mCherry and Cas9/GFP plasmids. We thank the Dana-Farber Cancer Institute Molecular Biology and Flow Cytometry Core Facilities, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core facility, Dana-Farber Cancer Institute Animal Resource Facilities and Translational Immunogenomics Laboratory for outstanding services. This research was supported by the National Cancer Institute (P01CA250959 to K.P. and H.W.L. and R35 CA197623 to K.P.), Ludwig Center at Harvard (to K.P.), Saverin Breast Cancer Research Fund (to K.P.), Canadian Institutes of Health Research (to M.-A.G.) and EMBO (to M.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.K.P. serves on the Scientific Advisory Board of and holds equity options in IDEAYA Biosciences and Scorpion Therapeutics. K.P. and H.W.L. receive sponsored research funding through the Dana-Farber Cancer Institute from Novartis. The remaining authors declare no competing interests.
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