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 WagleMyles Brown, Alexander Meissner, Piotr Sicinski, Jacob D. Jaffe, Rinath Jeselsohn, Alexander A. Gimelbrant, Franziska Michor, Kornelia Polyak

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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.

Original languageEnglish
Pages (from-to)939-953.e9
JournalCancer Cell
Issue number6
StatePublished - 10 Dec 2018
Externally publishedYes


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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


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