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Chemical profiling of the genome with anti-cancer drugs defines target specificities

ABSTRACT: Many anti-cancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors can also evict histones. We performed a genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II inhibitors. We show that different drugs target different types of chromatin for induction of DNA damage and histone eviction. Topoisomerase inhibitors topotecan and etoposide similarly target transcriptionally active chromatin for DNA damage. Daunorubicin induces DNA breaks and evicts histones in active chromatin, thus quenching local DNA damage response. The analog aclarubicin evicts histones in H3K27me3-marked heterochromatin. These results can guide rational treatment decisions regarding these genome manipulating anti-cancer drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60395 | GEO | 2015/05/10

SECONDARY ACCESSION(S): PRJNA258172

REPOSITORIES: GEO

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Chemical profiling of the genome with anti-cancer drugs defines target specificities

Project description:Many anti-cancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors can also evict histones. We performed a genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II inhibitors. We show that different drugs target different types of chromatin for induction of DNA damage and histone eviction. Topoisomerase inhibitors topotecan and etoposide similarly target transcriptionally active chromatin for DNA damage. Daunorubicin induces DNA breaks and evicts histones in active chromatin, thus quenching local DNA damage response. The analog aclarubicin evicts histones in H3K27me3-marked heterochromatin. These results can guide rational treatment decisions regarding these genome manipulating anti-cancer drugs. FAIRE-seq and g-H2AX ChIP-seq were performed on K562 cells after drug exposure

2015-05-10 | E-GEOD-60395 | biostudies-arrayexpress

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.

2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress

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

Project description: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.

2013-06-04 | E-GEOD-33633 | biostudies-arrayexpress

Genome-wide analysis of histone eviction by FAIRE-Seq

2013-06-04 | GSE33632 | GEO

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

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2013-06-04 | E-GEOD-33624 | biostudies-arrayexpress

Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 2)

Project description: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. As a result, the epigenome and the transcriptome are strongly affected. Tissue culture cells were treated with doxorubicin, aclarubicin or etoposide for 2 hours. Then drugs were removed by extensive washing. cells were further cultured for indicated days before total RNA were extracted and compared to un-treated control.

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Doxorubicin induces double-strand breaks at CpG island promoters

Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing. We have analyzed mouse squamous cell carcinoma cells treated with doxorubicin, aclarubicin and etoposide. The direct in situ Breaks Labeling, Enrichment on Streptavidin (BLESS, PMID 23503052) method was used for mapping DNA double-strand breaks genome-wide.

2015-01-31 | E-GEOD-62927 | biostudies-arrayexpress

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