Epigenetic changes in histone acetylation underpin resistance to the topoisomerase I inhibitor irinotecan.
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.
Mammalian Genome Stability Group, Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Western Bank, Sheffield, UK.|The Wellcome Trust DNA Repair Group, University of Sussex, Brighton, UK.
Cornelia
C
Meisenberg
Center for Genomics, Helmy Institute for Medical Sciences, Zewail City for Science and Technology, Giza, Egypt.|Mammalian Genome Stability Group, Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Western Bank, Sheffield, UK.
Mohamed E
ME
Ashour
Center for Genomics, Helmy Institute for Medical Sciences, Zewail City for Science and Technology, Giza, Egypt.
Lamia
L
El-Shafie
Mammalian Genome Stability Group, Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Western Bank, Sheffield, UK.
Chunyan
C
Liao
Mammalian Genome Stability Group, Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Western Bank, Sheffield, UK.
Adam
A
Hodgson
Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, UK.
Alice
A
Pilborough
Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, UK.
Syed A
SA
Khurram
Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
Jessica A
JA
Downs
Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
Simon E
SE
Ward
Center for Genomics, Helmy Institute for Medical Sciences, Zewail City for Science and Technology, Giza, Egypt.|Mammalian Genome Stability Group, Krebs and Sheffield Institute for Nucleic Acids, University of Sheffield, Western Bank, Sheffield, UK.|The Wellcome Trust DNA Repair Group, University of Sussex, Brighton, UK.
Sherif F
SF
El-Khamisy
D000107:Acetylation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008954:Models, Biological; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin