Drug-induced Histone Eviction From Open Chromatin Contributes to the Chemotherapeutic Effects of Doxorubicin

Nat Commun. 2013;4:1908. doi: 10.1038/ncomms2921.

Abstract

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aclarubicin / chemistry
  • Aclarubicin / pharmacology
  • Animals
  • Anthracyclines / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Blast Crisis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromatin / chemistry*
  • Chromatin / metabolism*
  • DNA / metabolism
  • DNA Damage
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology*
  • Etoposide / chemistry
  • Etoposide / pharmacology
  • Heart / drug effects
  • Histones / metabolism*
  • Humans
  • Intercalating Agents / pharmacology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Nude
  • Nucleic Acid Conformation*
  • Nucleosomes / drug effects
  • Nucleosomes / metabolism
  • Organ Specificity / drug effects
  • Transcriptome / genetics

Substances

  • Anthracyclines
  • Antineoplastic Agents
  • Chromatin
  • Histones
  • Intercalating Agents
  • Nucleosomes
  • Etoposide
  • Aclarubicin
  • Doxorubicin
  • DNA

Associated data

  • GEO/GSE33634