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

Nature Chemical Biology volume 11, pages 472–480 (2015)Cite this article

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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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References

  1. Arcamone, F.-M. Fifty years of chemical research at Farmitalia. Chemistry 15, 7774–7791 (2009).

    Article  CAS  Google Scholar 

  2. Pang, B. et al. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat. Commun. 4, 1908 (2013).

    Article  Google Scholar 

  3. Yang, F., Kemp, C.J. & Henikoff, S. Doxorubicin enhances nucleosome turnover around promoters. Curr. Biol. 23, 782–787 (2013).

    Article  CAS  Google Scholar 

  4. Jin, J. et al. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 14, 599–608 (2013).

    Article  CAS  Google Scholar 

  5. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  6. Gerstein, M.B. et al. Architecture of the human regulatory network derived from ENCODE data. Nature 489, 91–100 (2012).

    Article  CAS  Google Scholar 

  7. Nitiss, J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer 9, 338–350 (2009).

    Article  CAS  Google Scholar 

  8. Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer 6, 789–802 (2006).

    Article  CAS  Google Scholar 

  9. Kundaje, A. et al. Ubiquitous heterogeneity and asymmetry of the chromatin environment at regulatory elements. Genome Res. 22, 1735–1747 (2012).

    Article  CAS  Google Scholar 

  10. Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat. Genet. 41, 376–381 (2009).

    Article  CAS  Google Scholar 

  11. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  Google Scholar 

  12. Trojer, P. & Reinberg, D. Facultative heterochromatin: is there a distinctive molecular signature? Mol. Cell 28, 1–13 (2007).

    Article  CAS  Google Scholar 

  13. Gupta, J., Kumar, S., Li, J., Krishna Murthy Karuturi, R. & Tikoo, K. Histone H3 lysine 4 monomethylation (H3K4me1) and H3 lysine 9 monomethylation (H3K9me1): distribution and their association in regulating gene expression under hyperglycaemic/hyperinsulinemic conditions in 3T3 cells. Biochimie 94, 2656–2664 (2012).

    Article  CAS  Google Scholar 

  14. Beck, D.B., Oda, H., Shen, S.S. & Reinberg, D. PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 26, 325–337 (2012).

    Article  CAS  Google Scholar 

  15. Li, Z., Nie, F., Wang, S. & Li, L. Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc. Natl. Acad. Sci. USA 108, 3116–3123 (2011).

    Article  CAS  Google Scholar 

  16. de Jong, J. et al. Chromatin landscapes of retroviral and transposon integration profiles. PLoS Genet. 10, e1004250 (2014).

    Article  Google Scholar 

  17. Kuo, A.J. et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol. Cell 44, 609–620 (2011).

    Article  CAS  Google Scholar 

  18. Cao, R. & Zhang, Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED–EZH2 complex. Mol. Cell 15, 57–67 (2004).

    Article  CAS  Google Scholar 

  19. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  Google Scholar 

  20. Misteli, T. & Soutoglou, E. The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat. Rev. Mol. Cell Biol. 10, 243–254 (2009).

    Article  CAS  Google Scholar 

  21. Polo, S.E. & Jackson, S.P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

    Article  CAS  Google Scholar 

  22. Sperling, A.S., Jeong, K.S., Kitada, T. & Grunstein, M. Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast. Proc. Natl. Acad. Sci. USA 108, 12693–12698 (2011).

    Article  CAS  Google Scholar 

  23. Thakurela, S. et al. Gene regulation and priming by topoisomerase IIα in embryonic stem cells. Nat. Commun. 4, 2478 (2013).

    Article  Google Scholar 

  24. Sneeringer, C.J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. USA 107, 20980–20985 (2010).

    Article  CAS  Google Scholar 

  25. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6, 846–856 (2006).

    Article  CAS  Google Scholar 

  26. McCabe, M.T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

    Article  CAS  Google Scholar 

  27. Jaffe, J.D. et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45, 1386–1391 (2013).

    Article  CAS  Google Scholar 

  28. Pang, B. et al. Direct antigen presentation and gap junction mediated cross-presentation during apoptosis. J. Immunol. 183, 1083–1090 (2009).

    Article  CAS  Google Scholar 

  29. Staker, B.L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl. Acad. Sci. USA 99, 15387–15392 (2002).

    Article  CAS  Google Scholar 

  30. Tewey, K.M., Rowe, T., Yang, L., Halligan, B. & Liu, L. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226, 466–468 (1984).

    Article  CAS  Google Scholar 

  31. Frederick, C.A. et al. Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry 29, 2538–2549 (1990).

    Article  CAS  Google Scholar 

  32. Meuleman, W. et al. Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res. 23, 270–280 (2013).

    Article  CAS  Google Scholar 

  33. Sehouli, J. et al. Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J. Clin. Oncol. 26, 3176–3182 (2008).

    Article  CAS  Google Scholar 

  34. Vey, N. et al. Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study. Invest. New Drugs 17, 89–95 (1999).

    Article  CAS  Google Scholar 

  35. Lin, C.Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012).

    Article  CAS  Google Scholar 

  36. Timp, W. & Feinberg, A.P. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13, 497–510 (2013).

    Article  CAS  Google Scholar 

  37. Sehn, L.H. A decade of R-CHOP. Blood 116, 2000–2001 (2010).

    Article  CAS  Google Scholar 

  38. He, L.-R. et al. Prognostic impact of H3K27me3 expression on locoregional progression after chemoradiotherapy in esophageal squamous cell carcinoma. BMC Cancer 9, 461 (2009).

    Article  Google Scholar 

  39. Cai, M.Y. et al. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol. Med. 17, 12–20 (2011).

    Article  CAS  Google Scholar 

  40. Holm, K. et al. Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes. Mol. Oncol. 6, 494–506 (2012).

    Article  CAS  Google Scholar 

  41. Gaulton, K.J. et al. A map of open chromatin in human pancreatic islets. Nat. Genet. 42, 255–259 (2010).

    Article  CAS  Google Scholar 

  42. Schmidt, D. et al. ChIP-seq: using high-throughput sequencing to discover protein–DNA interactions. Methods 48, 240–248 (2009).

    Article  CAS  Google Scholar 

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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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  4. Lodewyk F A Wessels
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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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