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dc.contributor.authorMeisenberg, C
dc.contributor.authorAshour, ME
dc.contributor.authorEl-Shafie, L
dc.contributor.authorLiao, C
dc.contributor.authorHodgson, A
dc.contributor.authorPilborough, A
dc.contributor.authorKhurram, SA
dc.contributor.authorDowns, JA
dc.contributor.authorWard, SE
dc.contributor.authorEl-Khamisy, SF
dc.coverage.spatialEngland
dc.date.accessioned2022-08-24T12:00:24Z
dc.date.available2022-08-24T12:00:24Z
dc.date.issued2016-10-26
dc.identifiergkw1026
dc.identifier.citationNucleic Acids Research, 2016, pp. gkw1026 - gkw1026en_US
dc.identifier.issn0305-1048
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5322
dc.identifier.eissn1362-4962
dc.identifier.eissn1362-4962
dc.identifier.doi10.1093/nar/gkw1026
dc.description.abstractThe 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.
dc.format.extentgkw1026 - gkw1026
dc.languageeng
dc.language.isoengen_US
dc.publisherOxford University Press (OUP)en_US
dc.relation.ispartofNucleic Acids Research
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleEpigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-10-18
dc.date.updated2022-08-24T07:31:12Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1093/nar/gkw1026en_US
rioxxterms.licenseref.startdate2016-10-26
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttp://www.ncbi.nlm.nih.gov/pubmed/27789688
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Epigenetics and Genome Stability
pubs.publication-statusPublished online
icr.researchteamGenome Stabilityen_US
dc.contributor.icrauthorDowns, Jessica
icr.provenanceDeposited by Prof Jessica Downs on 2022-08-24. Deposit type is initial. No. of files: 1. Files: gkw1026.pdf


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