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Epigenetic changes due to histone eviction induced by anthracycline doxorubicin and aclarubicin

ABSTRACT: One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. Here, we compare three members of this class - the antracyclines doxorubicin and aclarubicin, and a chemically unrelated compound, etoposide. Aclarubicin does not induce DNA breaks. We define a new activity for the antracyclines: unsupported histone eviction from ´open´ or loosely packed chromosomal areas reflecting exon and promoter regions. Comparison of histone H3K4me3 of cells post topoisomerase II inhibitors treatment to un-treated ones by ChIP-seq. Comparison of phosphorylated histone H2AX of cells post topoisomerase II inhibitors doxorubicin and etoposide treatment to un-treated ones by ChIP-seq.

ORGANISM(S): Homo sapiens

SUBMITTER: Baoxu Pang

PROVIDER: E-GEOD-33633 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Pang Baoxu B Qiao Xiaohang X Janssen Lennert L Velds Arno A Groothuis Tom T Kerkhoven Ron R Nieuwland Marja M Ovaa Huib H Rottenberg Sven S van Tellingen Olaf O Janssen Jeroen J Huijgens Peter P Zwart Wilbert W Neefjes Jacques J

Nature communications 20130101

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 respons ...[more]

PMID: 23715267

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Genome-wide analysis of histone eviction by FAIRE-Seq

Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.

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Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 1)

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Doxorubicin induces double-strand breaks at CpG island promoters

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