Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin

Baoxu Pang, Xiaohang Qiao, Lennert Janssen, Arno Velds, Tom Groothuis, Ron Kerkhoven, Marja Nieuwland, Huib Ovaa, Sven Rottenberg, Olaf van Tellingen, Jeroen Janssen, Peter Huijgens, Wilbert Zwart and Jacques Neefjes ()
Additional contact information
Baoxu Pang: The Netherlands Cancer Institute
Xiaohang Qiao: The Netherlands Cancer Institute
Lennert Janssen: The Netherlands Cancer Institute
Arno Velds: Central Genomic Facility, The Netherlands Cancer Institute
Tom Groothuis: The Netherlands Cancer Institute
Ron Kerkhoven: Central Genomic Facility, The Netherlands Cancer Institute
Marja Nieuwland: Central Genomic Facility, The Netherlands Cancer Institute
Huib Ovaa: The Netherlands Cancer Institute
Sven Rottenberg: The Netherlands Cancer Institute
Olaf van Tellingen: The Netherlands Cancer Institute
Jeroen Janssen: VU University Medical Center
Peter Huijgens: VU University Medical Center
Wilbert Zwart: The Netherlands Cancer Institute
Jacques Neefjes: The Netherlands Cancer Institute

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2921

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