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.

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
  • 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*
  • Whole Exome Sequencing / methods

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