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Cited by 59Cancer therapeutics and mechanismsHistone Deacetylase Inhibitors ResearchGenomics and Chromatin Dynamics

Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan

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Meisenberg, Cornelia, Ashour, Mohamed E., El-Shafie, Lamia, Liao, Chunyan, Hodgson, Adam, Pilborough, Alice, Khurram, Syed A., Downs, Jessica A. +2 more·2016·Nucleic Acids Research
DOI 10.1093/nar/gkw1026PMC PMC5388393
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Abstract

The topoisomerase I (TOP1) inhibitor irinotecan triggers cell death by trapping TOP1 on DNA, generating cytotoxic protein-linked DNA breaks (PDBs). Despite its wide application in a variety of solid tumors, the mechanisms of cancer cell resistance to irinotecan remains poorly understood. Here, we generated colorectal cancer (CRC) cell models for irinotecan resistance and report that resistance is neither due to downregulation of the main cellular target of irinotecan TOP1 nor upregulation of the key TOP1 PDB repair factor TDP1. Instead, the faster repair of PDBs underlies resistance, which is associated with perturbed histone H4K16 acetylation. Subsequent treatment of irinotecan-resistant, but not parental, CRC cells with histone deacetylase (HDAC) inhibitors can effectively overcome resistance. Immunohistochemical analyses of CRC tissues further corroborate the importance of histone H4K16 acetylation in CRC. Finally, the resistant clones exhibit cross-resistance with oxaliplatin but not with ionising radiation or 5-fluoruracil, suggesting that the latter two could be employed following loss of irinotecan response. These findings identify perturbed chromatin acetylation in irinotecan resistance and establish HDAC inhibitors as potential therapeutic means to overcome resistance.

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  • Inhibiting HDACs can overcome resistance to chemotherapy-induced DNA damage in CRC cells by different molecular mechanisms, such as downregulating thymidylate synthase gene expression or modifying chromatin condensation, and subsequently inducing cell death.

    “Mechanistically, various studies suggest that inhibiting HDACs can overcome resistance to chemotherapy-induced DNA damage in CRC cells by different molecular mechanisms, such as downregulating thymidylate synthase gene expression or modifying chromatin condensation, and subsequently inducing cell death [58,59,165].”

    From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [59]

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  • Alterations in histone modifications can regulate gene expression and chromatin structure, further contributing to resistance against chemotherapy drugs.

    “Alterations in histone modifications can regulate gene expression and chromatin structure, further contributing to resistance against chemotherapy drugs [57,58,59].”

    From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [59]

    The Discussion (page not specified) links reduced histone H4K16 acetylation to altered DNA repair and irinotecan resistance, supporting the role of histone modifications in chemotherapy resistance. It does not establish that regulation of gene expression contributes to that resistance; instead, it reports no change in the levels of the examined DNA-repair factors. (LLM, conf=0.86)

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  1. [1]Wang J.C. DNA topoisomerases. Annu. Rev. Biochem. 1996; 65: 635– 692. 8811192
  2. [2]Stewart L., Redinbo M.R., Qiu X., Hol W.G., Champoux J.J. A model for the mechanism of human topoisomerase I. Science. 1998; 279: 1534– 1541. 9488652
  3. [3]El-Khamisy S.F. To live or to die: a matter of processing damaged DNA termini in neurons. EMBO Mol. Med. 2011; 3: 78– 88. 21246735 PMC3377058
  4. [4]Nitiss J.L., Wang J.C. Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol. Pharmacol. 1996; 50: 1095– 1102. 8913340
  5. [5]Pommier Y. DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem. Rev. 2009; 109: 2894– 2902. 19476377 PMC2707511
  6. [6]Ashour M.E., Atteya R., El-Khamisy S.F. Topoisomerase-mediated chromosomal break repair: an emerging player in many games. Nat. Rev. Cancer. 2015; 15: 137– 151. 25693836
  7. [7]Hudson J.J.R., Chiang S.-C., Wells O.S., Rookyard C., El-Khamisy S.F. SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nat. Commun. 2012; 3: 733– 713. 22415824 PMC3316882
  8. [8]Desai S.D. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J. Biol. Chem. 1997; 272: 24159– 24164. 9305865
  9. [9]El-Khamisy S.F., Saifi G.M., Weinfeld M., Johansson F., Helleday T., Lupski J.R., Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature. 2005; 434: 108– 113. 15744309
  10. [10]Interthal H., Chen H.J., Kehl-Fie T.E., Zotzmann J., Leppard J.B., Champoux J.J. SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 2005; 24: 2224– 2233. 15920477 PMC1150888
  11. [11]Miao Z.-H., Agama K., Sordet O., Povirk L., Kohn K.W., Pommier Y. Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes. DNA Repair (Amst.). 2006; 5: 1489– 1494. 16935573
  12. [12]Alagoz M., Wells O.S., El-Khamisy S.F. TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy. Nucleic Acids Res. 2014; 42: 3089– 3103. 24335147 PMC3950670
  13. [13]Katyal S., El-Khamisy S.F., Russell H.R., Li Y., Ju L., Caldecott K.W., McKinnon P.J. TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J. 2007; 26: 4720– 4731. 17914460 PMC2080805
  14. [14]Das B.B., Huang S.-Y.N., Murai J., Rehman I., Amé J.-C., Sengupta S., Das S.K., Majumdar P., Zhang H., Biard D. PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. Nucleic Acids Res. 2014; 42: 4435– 4449. 24493735 PMC3985661
  15. [15]Zeng Z., Sharma A., Ju L., Murai J., Umans L., Vermeire L., Pommier Y., Takeda S., Huylebroeck D., Caldecott K.W. TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic Acids Res. 2012; 40: 8371– 8380. 22740648 PMC3458563
  16. [16]Chaudhuri A.R., Hashimoto Y., Herrador R., Neelsen K.J., Fachinetti D., Bermejo R., Cocito A., Costanzo V., Lopes M. Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat. Struct. Mol. Biol. 2012; 19: 417– 423. 22388737
  17. [17]Berti M., Chaudhuri A.R., Thangavel S., Gomathinayagam S., Kenig S., Vujanovic M., Odreman F., Glatter T., Graziano S., Mendoza-Maldonado R. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat. Struct. Mol. Biol. 2013; 20: 347– 354. 23396353 PMC3897332
  18. [18]Zellweger R., Dalcher D., Mutreja K., Berti M., Schmid J.A., Herrador R., Vindigni A., Lopes M. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J. Cell Biol. 2015; 208: 563– 579. 25733714 PMC4347635
  19. [19]Strumberg D., Pilon A.A., Smith M., Hickey R., Malkas L., Pommier Y. Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5΄-phosphorylated DNA double-strand breaks by replication runoff. Mol. Cell. Biol. 2000; 20: 3977– 3987. 10805740 PMC85758
  20. [20]Sordet O., Nakamura A.J., Redon C.E., Pommier Y. DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions. Cell Cycle. 2010; 9: 274– 278. 20023421 PMC7289056
  21. [21]Huang X., Traganos F., Darzynkiewicz Z. DNA damage induced by DNA topoisomerase I- and topoisomerase II-inhibitors detected by histone H2AX phosphorylation in relation to the cell cycle phase and apoptosis. Cell Cycle. 2003; 2: 614– 619. 14504478
  22. [22]Alagoz M., Chiang S.-C., Sharma A., El-Khamisy S.F. ATM deficiency results in accumulation of DNA-topoisomerase I covalent intermediates in neural cells. PLoS ONE. 2013; 8: e58239. 23626666 PMC3634035
  23. [23]Regairaz M., Zhang Y.-W., Fu H., Agama K.K., Tata N., Agrawal S., Aladjem M.I., Pommier Y. Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I-DNA complexes. J. Cell Biol. 2011; 195: 739– 749. 22123861 PMC3257568
  24. [24]Kim Y., Spitz G.S., Veturi U., Lach F.P., Auerbach A.D., Smogorzewska A. Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4. Blood. 2013; 121: 54– 63. 23093618 PMC3538331
  25. [25]Gilbert D.C., Chalmers A.J., El-Khamisy S.F. Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets. Br. J. Cancer. 2011; 106: 18– 24. 22108516 PMC3251848
  26. [26]Zhang Y.W., Regairaz M., Seiler J.A., Agama K.K., Doroshow J.H., Pommier Y. Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Nucleic Acids Res. 2011; 39: 3607– 3620. 21227924 PMC3089458
  27. [27]Maede Y., Shimizu H., Fukushima T., Kogame T., Nakamura T., Miki T., Takeda S., Pommier Y., Murai J. Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel. Mol. Cancer Ther. 2014; 13: 214– 220. 24130054 PMC3919527
  28. [28]Hartsuiker E., Neale M.J., Carr A.M. Short article. Mol. Cell. 2009; 33: 117– 123. 19150433 PMC2675033
  29. [29]Alagoz M., Gilbert D.C., El-Khamisy S., Chalmers A.J. DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets. Curr. Med. Chem. 2012; 19: 3874– 3885. 22788763
  30. [30]Zheng Y., Zhou J., Tong Y. Gene signatures of drug resistance predict patient survival in colorectal cancer. Pharmacogenomics J. 2014; 15: 135– 143. 25179828 PMC4381104
  31. [31]Jensen N.F., Stenvang J., Beck M.K., Hanáková B., Belling K.C., Do K.N., Viuff B., Nygård S.B., Gupta R., Rasmussen M.H. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: towards a predictive signature of chemoresistance. Mol. Oncol. 2015; 9: 1169– 1185. 25759163 PMC5528766
  32. [32]Arnaud O., Boumendjel A., Gèze A., Honorat M., Matera E.L., Guitton J., Stein W.D., Bates S.E., Falson P., Dumontet C. The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan. Eur. J. Cancer. 2011; 47: 640– 648. 21216589 PMC6936733
  33. [33]Zander S.A.L., Kersbergen A., van der Burg E., de Water N., van Tellingen O., Gunnarsdottir S., Jaspers J.E., Pajic M., Nygren A.O.H., Jonkers J. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 2010; 70: 1700– 1710. 20145144
  34. [34]Mazard T., Causse A., Simony J., Leconet W., Vezzio-Vié N., Torro A., Jarlier M., Evrard A., Del Rio M., Assenat E. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump. Mol. Cancer Ther. 2013; 12: 2121– 2134. 23960095
  35. [35]Tomicic M.T., Kaina B. Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim. Biophys. Acta. 2013; 1835: 11– 27. 23006513
  36. [36]Proszek J., Roy A., Jakobsen A.-K., Frøhlich R., Knudsen B.R., Stougaard M. Topoisomerase I as a biomarker: detection of activity at the single molecule level. Sensors (Basel). 2013; 14: 1195– 1207. PMC3926610 24434877
  37. [37]Meisenberg C., Gilbert D.C., Chalmers A., Haley V., Gollins S., Ward S.E., El-Khamisy S.F. Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. Mol. Cancer Ther. 2015; 14: 575– 585. 25522766 PMC4340569
  38. [38]Liu C., Zhou S., Begum S., Sidransky D., Westra W.H., Brock M., Califano J.A. Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer. Lung Cancer. 2007; 55: 303– 311. 17118488 PMC1890013
  39. [39]Barthelmes H.U., Habermeyer M., Christensen M.O., Mielke C., Interthal H., Pouliot J.J., Boege F., Marko D. TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II. J. Biol. Chem. 2004; 279: 55618– 55625. 15494395
  40. [40]Schmittgen T.D., Livak K.J. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc. 2008; 3: 1101– 1108. 18546601
  41. [41]Breslin C., Clements P.M., El-Khamisy S.F., Petermann E., Iles N., Caldecott K.W. Measurement of chromosomal DNA single-strand breaks and replication fork progression rates. Meth. Enzymol. 2006; 409: 410– 425. 16793415
  42. [42]Khurram S.A., Whawell S.A., Bingle L., Murdoch C., McCabe B.M., Farthing P.M. Functional expression of the chemokine receptor XCR1 on oral epithelial cells. J. Pathol. 2010; 221: 153– 163. 20225245
  43. [43]Jensen E.C. Quantitative analysis of histological staining and fluorescence using ImageJ. Anat. Rec. (Hoboken). 2013; 296: 378– 381. 23382140
  44. [45]Wood J.P., Smith A.J.O., Bowman K.J., Thomas A.L., Jones G.D.D. Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo. Cancer Med. 2015; doi:10.1002/cam4.477. PMC4567016 26108357 · DOI
  45. [46]Gómez-Herreros F., Schuurs-Hoeijmakers J.H.M., McCormack M., Greally M.T., Rulten S., Romero-Granados R., Counihan T.J., Chaila E., Conroy J., Ennis S. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat. Genet. 2014; 46: 516– 521. 24658003
  46. [47]Elsayed W., El-Shafie L., Hassan M.K., Farag M.A., El-Khamisy S.F. Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1. Sci. Rep. 2016; 6: 1– 10. 27220325 PMC4879542
  47. [48]Pommier Y., Pourquier P., Fan Y., Strumberg D. Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim. Biophys. Acta. 1998; 1400: 83– 105. 9748515
  48. [49]McCabe N., Turner N.C., Lord C.J., Kluzek K., Bialkowska A., Swift S., Giavara S., O'Connor M.J., Tutt A.N., Zdzienicka M.Z. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006; 66: 8109– 8115. 16912188
  49. [50]Venkitaraman A.R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002; 108: 171– 182. 11832208
  50. [51]Deans A.J., West S.C. DNA interstrand crosslink repair and cancer. Nat. Rev. Cancer. 2011; 11: 467– 480. 21701511 PMC3560328
  51. [52]Jones R.M., Kotsantis P., Stewart G., Groth P., Petermann E. BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. Mol. Cancer Ther. 2014; 13: 2412– 2421. 25053826 PMC4185294
  52. [54]Price B.D., D'Andrea A.D. Chromatin remodeling at DNA double-strand breaks. Cell. 2013; 152: 1344– 1354. 23498941 PMC3670600
  53. [55]Botuyan M.V., Lee J., Ward I.M., Kim J.-E., Thompson J.R., Chen J., Mer G. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006; 127: 1361– 1373. 17190600 PMC1804291
  54. [56]Sanders S.L., Portoso M., Mata J., Bähler J., Allshire R.C., Kouzarides T. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell. 2004; 119: 603– 614. 15550243
  55. [57]Bothmer A., Robbiani D.F., Di Virgilio M., Bunting S.F., Klein I.A., Feldhahn N., Barlow J., Chen H.-T., Bosque D., Callen E. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol. Cell. 2011; 42: 319– 329. 21549309 PMC3142663
  56. [58]Bunting S.F., Callen E., Wong N., Chen H.-T., Polato F., Gunn A., Bothmer A., Feldhahn N., Fernandez-Capetillo O., Cao L. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010; 141: 243– 254. 20362325 PMC2857570
  57. [59]Bouwman P., Aly A., Escandell J.M., Pieterse M., Bartkova J., van der Gulden H., Hiddingh S., Thanasoula M., Kulkarni A., Yang Q. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 2010; 17: 688– 695. 20453858 PMC2912507
  58. [60]Chapman J., Taylor M.R.G., Boulton S.J. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell. 2012; 47: 497– 510. 22920291
  59. [61]Sharma G.G., So S., Gupta A., Kumar R., Cayrou C., Avvakumov N., Bhadra U., Pandita R.K., Porteus M.H., Chen D.J. MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol. Cell. Biol. 2010; 30: 3582– 3595. 20479123 PMC2897562
  60. [62]Li X., Corsa C.A.S., Pan P.W., Wu L., Ferguson D., Yu X., Min J., Dou Y. MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol. Cell. Biol. 2010; 30: 5335– 5347. 20837706 PMC2976376
  61. [63]Beck C., Robert I., Reina-San-Martin B., Schreiber V., Dantzer F. Poly(ADP-ribose) polymerases in double-strand break repair: focus on PARP1, PARP2 and PARP3. Exp. Cell Res. 2014; 329: 18– 25. 25017100
  62. [64]Fraga M.F., Ballestar E., Villar-Garea A., Boix-Chornet M., Espada J., Schotta G., Bonaldi T., Haydon C., Ropero S., Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 2005; 37: 391– 400. 15765097

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Authors
Meisenberg, C., Ashour, M. E., El-Shafie, L., Liao, C., Hodgson, A., Pilborough, A., Khurram, S. A., Downs, J. A., Ward, S. E., & El-Khamisy, S. F.
Affiliations
  • University of Sussex (GB)
  • Zewail City of Science and Technology (EG)
  • University of Sheffield (GB)
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2016-10-26
Volume
45
Issue
3
Pages
gkw1026
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkw1026
PMC
PMC5388393
OpenAlex
W2540793423
Cited by
59
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 10 · 2023: 10 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 1
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
Funders
  • Wellcome Trust (103844, 103844/Z/14/Z)
  • National Institute for Health and Care Research (CL-2010-04-004)
  • University of Sheffield (103844)
  • Lister Institute of Preventive Medicine
  • Medical Research Council (MR/N02155X/1, MR/N02155X/2)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
irinotecan resistance, topoisomerase I inhibitor, histone H4K16 acetylation, histone deacetylase inhibitors, TDP1, DNA repair, colorectal cancer, epigenetic regulation, chromatin acetylation
MeSH terms
Irinotecan, Acetylation, Camptothecin, DNA Repair, DNA Topoisomerases, Type I, Histones, Humans, Models, Biological, Phosphoric Diester Hydrolases, Colorectal Neoplasms, Drug Resistance, Neoplasm, Epigenesis, Genetic, Cell Line, Tumor, DNA Breaks, Double-Stranded, Histone Deacetylase Inhibitors, Topoisomerase I Inhibitors

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