KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Kunihiko Hinohara; Hua-Jun Wu; Sébastien Vigneau; Thomas O McDonald; Kyomi J Igarashi; Kimiyo N Yamamoto; Thomas Madsen; Anne Fassl; Shawn B Egri; Malvina Papanastasiou; Lina Ding; Guillermo Peluffo; Ofir Cohen; Stephen C Kales; Madhu Lal-Nag; Ganesha Rai; David J Maloney; Ajit Jadhav; Anton Simeonov; Nikhil Wagle; Myles Brown; Alexander Meissner; Piotr Sicinski; Jacob D Jaffe; Rinath Jeselsohn; Alexander A Gimelbrant; Franziska Michor; Kornelia Polyak

doi:10.1016/j.ccell.2018.10.014

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

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

Authors

Kunihiko Hinohara¹, Hua-Jun Wu², Sébastien Vigneau³, Thomas O McDonald⁴, Kyomi J Igarashi³, Kimiyo N Yamamoto², Thomas Madsen², Anne Fassl³, Shawn B Egri⁵, Malvina Papanastasiou⁵, Lina Ding¹, Guillermo Peluffo¹, Ofir Cohen⁶, Stephen C Kales⁷, Madhu Lal-Nag⁷, Ganesha Rai⁷, David J Maloney⁷, Ajit Jadhav⁷, Anton Simeonov⁷, Nikhil Wagle⁸, Myles Brown⁹, Alexander Meissner¹⁰, Piotr Sicinski³, Jacob D Jaffe⁵, Rinath Jeselsohn¹, Alexander A Gimelbrant³, Franziska Michor¹¹, Kornelia Polyak¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / drug therapy
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Estradiol / pharmacology
Estrogen Receptor Modulators / pharmacology
Exome Sequencing / methods
Female
Fulvestrant / pharmacology
Genetic Heterogeneity
Humans
Jumonji Domain-Containing Histone Demethylases / genetics*
Jumonji Domain-Containing Histone Demethylases / metabolism
MCF-7 Cells
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Retinoblastoma-Binding Protein 2 / genetics*
Retinoblastoma-Binding Protein 2 / metabolism
Transcriptome / drug effects
Transcriptome / genetics*

Substances

Estrogen Receptor Modulators
Nuclear Proteins
Repressor Proteins
Fulvestrant
Estradiol
Jumonji Domain-Containing Histone Demethylases
KDM5A protein, human
KDM5B protein, human
Retinoblastoma-Binding Protein 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding