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Updated: Feb 2, 2026

Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity
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Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity

Published on: March 11, 2012

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KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Kunihiko Hinohara1, Hua-Jun Wu2, Sébastien Vigneau3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Cancer Cell
|November 26, 2018
PubMed

Insights

KDM5A/B demethylases drive endocrine resistance in breast cancer by increasing cellular heterogeneity. Inhibiting KDM5 enhances anti-estrogen sensitivity, revealing KDM5A/B as key regulators of therapeutic resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The KDM5 histone demethylase family is linked to therapeutic resistance, notably endocrine resistance in breast cancer.
  • The precise mechanisms underlying this resistance are not well understood.

Purpose of the Study:

  • To investigate the role of KDM5A/B in endocrine resistance in breast cancer.
  • To explore the impact of KDM5 inhibition on estrogen receptor (ER) signaling and cellular heterogeneity.

Main Methods:

  • Genetic deletion of KDM5A/B and KDM5 activity inhibition.
  • Analysis of estrogen receptor (ER) signaling pathways.
  • Single-cell RNA sequencing and cellular barcoding.
  • Mathematical modeling of cellular dynamics.

Main Results:

  • KDM5A/B deletion or inhibition increases sensitivity to anti-estrogens.
  • KDM5 activity modulates ER signaling and reduces cellular transcriptomic heterogeneity.
  • Higher KDM5B expression correlates with increased heterogeneity and poorer prognosis in ER+ breast tumors.
  • Endocrine resistance arises from selection of pre-existing cells, while KDM5 inhibitor resistance is acquired.

Conclusions:

  • KDM5A/B are critical regulators of cellular phenotypic heterogeneity in breast cancer.
  • Targeting KDM5A/B may overcome endocrine resistance by reducing heterogeneity and modulating ER signaling.
  • Understanding KDM5's role in heterogeneity is crucial for developing more effective breast cancer therapies.
Keywords:
KDM5Bacquired resistancebarcodingcellular heterogeneityendocrine resistanceepigeneticpre-existing resistancesingle-cell RNA-seqsubclonal fractiontranscriptomic heterogeneity

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