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

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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.

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Figure 1: Different anthracycline drugs induce histone eviction from unique chromatin regions.
Figure 2: Unique chromatin features and states are associated with drug-induced histone eviction.
Figure 3: Chromatin features and states associate with γ-H2AX induced by TopoI and TopoII inhibitors.
Figure 4: Loss of γ-H2AX DNA damage signal is related to histone eviction during Daun treatment.
Figure 5: DLBCL tumors accumulating H3K27me3 modifications are more sensitive to Acla exposure.

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Acknowledgements

We thank R. Kerkhoven, M. Nieuwland and A. Velds of the Netherlands Cancer Institute Genomic Core Facility; L. Janssen for support in cloning; and W. Akhtar, J. Gruber, B. van Steensel and P. Borst for their critical reading of the manuscript. This work was supported by a European Research Council grant to J.N. J.N. is a member of the Institute of Chemical Immunology.

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Author notes

  1. Baoxu Pang, Johann de Jong and Xiaohang Qiao: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    Baoxu Pang, Xiaohang Qiao & Jacques Neefjes

  2. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    Johann de Jong & Lodewyk F A Wessels

  3. Institute for Chemical Immunology, the Netherlands

    Jacques Neefjes

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  1. Baoxu Pang
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  2. Johann de Jong
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  3. Xiaohang Qiao
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  4. Lodewyk F A Wessels
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  5. Jacques Neefjes
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Contributions

B.P. and J.N. designed experiments. X.Q. and B.P. performed experiments. J.d.J. designed and implemented the computational methods. J.d.J. and B.P. analyzed the data. B.P., J.d.J. and J.N. drafted the manuscript with input from all authors. J.N. and L.F.A.W. supervised the study and analyses.

Corresponding authors

Correspondence to Baoxu Pang, Lodewyk F A Wessels or Jacques Neefjes.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1, Supplementary Figures 1–19 and Supplementary Note. (PDF 18217 kb)

Supplementary Video 1

Histone dynamics in cells exposed to the TopoI inhibitor topotecan. (AVI 6394 kb)

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Pang, B., de Jong, J., Qiao, X. et al. Chemical profiling of the genome with anti-cancer drugs defines target specificities. Nat Chem Biol 11, 472–480 (2015). https://doi.org/10.1038/nchembio.1811

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