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

Meisenberg, Cornelia, Ashour, Mohamed E., El-Shafie, Lamia, Liao, Chunyan, Hodgson, Adam, Pilborough, Alice, Khurram, Syed A., Downs, Jessica A., Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377 and El-Khamisy, Sherif F. 2017. Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan. Nucleic Acids Research 45 (3) , pp. 1159-1176. 10.1093/nar/gkw1026

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
Publisher:	Oxford University Press
ISSN:	0305-1048
Date of First Compliant Deposit:	22 February 2018
Date of Acceptance:	18 October 2016
Last Modified:	05 May 2023 00:28
URI:	https://orca.cardiff.ac.uk/id/eprint/109272

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