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Topoisomerase II inhibitors and histone eviction

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Baoxu Pang

PROVIDER: E-GEOD-33634 | 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

Similar Datasets

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

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

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

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.

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.

2013-06-04 | E-GEOD-33625 | biostudies-arrayexpress

Predicting drug response in human prostate cancer from preclinical analysis of in vivo mouse models (I)

Project description:Analysis of the transcriptome of mouse models of prostate cancer after treatment with rapamycin and PD0325901 combination therapy or standard of care docetaxel. The Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+ (NPK mice) was used in this study. Two months after tumor induction, mice were randomly assigned to vehicle (Veh) or treatments groups, such as rapamycin and PD0325901 (RAPPD) or docetaxel (Docetaxel). For the treatment groups mice were administered rapamycin (10 mg/kg) and PD0325901 (10 mg/kg) or docetaxel (10 mg/kg) for 5 days (SHORT) or for 1 month (LONG). At the end of the treatment, mice were euthanized, tumors harvested and snap frozen for subsequent molecular analysis. Total RNA obtained from prostate tumors/tissues. Prostate tumors/tissues were harvested and processed for RNA isolation and transcriptome analysis using the MagMAX RNA isolation kit (Ambion). Total RNA was amplified and labelled for subsequent microarrays hybridization using the Illumina TotalPrep RNA Amplification Kit.

2015-09-17 | E-GEOD-69211 | biostudies-arrayexpress

Predicting drug response in human prostate cancer from preclinical analysis of in vivo mouse models (II)

Project description:Analysis of the transcriptome of allografted mouse tumors after treatment with rapamycin and PD0325901. Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+ (NPK mice) were induced and their tumors removed to generate allograft lines by implanting a 1.5 mm3 tumor fragment in the subcutaneous space of athymic nude mice. Allografted NPK tumors were allowed to grow until they reached a volume of 1 cm3, at which moment they were randomly assigned to either vehicle (Veh) or combination therapy using rapamycin and PD0325901 (RAPPD). Allografted mice were administered rapamycin (10 mg/kg) and PD0325901 (10 mg/kg) during five consecutive days (Allo SHORT). Mice were euthanized in the fifth day 6 hours after having received the last treatment and the tumors were harvested and snap frozen for subsequent molecular analysis. Total RNA obtained from prostate tumors/tissues. Prostate tumors/tissues were harvested and processed for RNA isolation and transcriptome analysis using the MagMAX RNA isolation kit (Ambion). Total RNA was amplified and labelled for subsequent microarrays hybridization using the Illumina TotalPrep RNA Amplification Kit.

2015-09-17 | E-GEOD-69213 | biostudies-arrayexpress

Predicting drug response in human prostate cancer from preclinical analysis of in vivo mouse models

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-17 | E-GEOD-69214 | biostudies-arrayexpress

Cross-species analysis of genome-wide regulatory networks identifies a synergistic dependency between FOXM1 and CENPF that drives prostate cancer malignancy

Project description:Analysis of the transcriptome of mouse models of prostate cancer to assemble a mouse prostate cancer interactome. To assemble the mouse prostate cancer interactome, we collected 13 distinct mice or genetically-engineered mouse models (GEMMs), which together represent the full spectrum of prostate cancer phenotypes including: normal epithelium (i.e., wild-type), low-grade PIN (i.e., Nkx3.1 and APT), high-grade PIN and adenocarcinoma (i.e., APT-P; APC; Myc; NP; Erg-P; and NP53), castration-resistant prostate cancer (i.e., NP-AI), and metastatic prostate cancer (i.e., NPB; NPK; and TRAMP). To further enhance the heterogeneity afforded by this diversity of mouse models, we pharmacologically perturbed each GEMM using 13 different drugs (or appropriate vehicle). The resulting mouse prostate tissue/tumor dataset encompassed 384 expression profiles Total RNA obtained from prostate tumors/tissues of 13 mouse models of prostate cancer treated with 13 different drugs for 5 consecutive days. Prostate tumors/tissues were harvested and processed for RNA isolation and transcriptome analysis.

2014-05-12 | E-GEOD-53202 | biostudies-arrayexpress

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Project description:The stress sensors ATF6, IRE1 and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to re-establish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, sugars or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized. Here, we compared gene and protein expression profiles in cells challenged with ER stress-inducing drugs or expressing model polypeptides. Drugs titration to limit up-regulation of the endogenous ER stress reporters BiP/HSPA5 and HERP/HERPUD1 to levels comparable to luminal accumulation of unfolded proteins substantially reduced the amplitude of transcriptional and translational responses. Nevertheless, these remained pleiotropic and failed to recapitulate responses to ER load with unfolded proteins, which induced a limited subset of genes participating in a chaperone complex that binds unfolded chains.

2018-02-16 | PXD008529 | Pride

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