title: Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin.
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.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands.
authors.forename: Baoxu
authors.initials: B
authors.lastname: Pang
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Qiao
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.forename: Arno
authors.initials: A
authors.lastname: Velds
authors.forename: Tom
authors.initials: T
authors.lastname: Groothuis
authors.forename: Ron
authors.initials: R
authors.lastname: Kerkhoven
authors.forename: Marja
authors.initials: M
authors.lastname: Nieuwland
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Janssen
authors.forename: Peter
authors.initials: P
authors.lastname: Huijgens
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D015250:Aclarubicin / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D007364:Intercalating Agents; D009707:Nucleosomes; D005047:Etoposide; D015250:Aclarubicin; D004317:Doxorubicin; D004247:DNA