Abstract
Many anticancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors additionally cause histone eviction. Here, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. The TopoI inhibitor topotecan and the TopoII inhibitor etoposide are similar in inducing DNA damage at transcriptionally active genomic regions. The anthracycline daunorubicin induces DNA breaks and evicts histones from active chromatin, thus quenching local DNA damage responses. Another anthracycline, aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aclarubicin / chemistry
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Aclarubicin / pharmacology
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Chromatin / chemistry
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Chromatin / drug effects
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Chromatin / metabolism
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DNA Damage
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DNA, Neoplasm / chemistry*
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DNA, Neoplasm / metabolism
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Daunorubicin / chemistry
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Daunorubicin / pharmacology
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Etoposide / chemistry
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Etoposide / pharmacology
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Gene Expression Regulation, Neoplastic*
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Genome, Human*
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Histones / antagonists & inhibitors
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Histones / chemistry
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Histones / genetics
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Histones / metabolism
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Humans
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Molecular Targeted Therapy
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Neoplasms / chemistry
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / pathology
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Organ Specificity
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Protein Transport / drug effects
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Structure-Activity Relationship
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Topoisomerase Inhibitors / chemistry
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Topoisomerase Inhibitors / pharmacology*
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Topotecan / chemistry
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Topotecan / pharmacology
Substances
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Antineoplastic Agents
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Chromatin
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DNA, Neoplasm
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H2AX protein, human
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Histones
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Topoisomerase Inhibitors
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Etoposide
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Aclarubicin
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Topotecan
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Daunorubicin