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Cancer Cell. 2018 Dec 10;34(6):939-953.e9. doi: 10.1016/j.ccell.2018.10.014. Epub 2018 Nov 21.

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
7
National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA.
10
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
11
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Ludwig Center at Harvard, Boston, MA 02215, USA. Electronic address: michor@jimmy.harvard.edu.
12
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Abstract

Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.

KEYWORDS:

KDM5B; acquired resistance; barcoding; cellular heterogeneity; endocrine resistance; epigenetic; pre-existing resistance; single-cell RNA-seq; subclonal fraction; transcriptomic heterogeneity

PMID:
30472020
PMCID:
PMC6310147
[Available on 2019-12-10]
DOI:
10.1016/j.ccell.2018.10.014
[Indexed for MEDLINE]

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