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.
Highlights
Irinotecan is converted into its active form SN-38, which is a camptothecin (CPT)-based agent that promotes cancer cell death by interfering with the topoisomerase type 1 enzyme (TOP1) [1]
We report that the mechanism of resistance onset is not due to deregulation of TOP1 or tyrosyl DNA phosphodiesterase 1 (TDP1) but due to improved DNA double-strand break (DSB) repair as observed in multiple independently generated irinotecan-resistant clones
The increased DNA DSB repair rate was due to changes in the chromatin acetylation landscape, in particular H4K16ac, and subsequent inhibition of histone deacetylases selectively sensitized irinotecanresistant but not parental cells
Summary
Irinotecan is converted into its active form SN-38, which is a camptothecin (CPT)-based agent that promotes cancer cell death by interfering with the topoisomerase type 1 enzyme (TOP1) [1]. If an advancing replication fork encounters a TOP1cc or an unrepaired TOP1-PDB on the leading strand, the forks are reversed and stabilised by PARP1 to allow time for the removal of TOP1-PDBs [16], a process that is negatively regulated through the RecQ1 helicase [17,18]. TOP1 can be removed from TOP1-PDBs by nucleolytic cleavage of DNA, removing TOP1 and a stretch of DNA to which it is attached This is conducted by a number of nucleases including the Mus81-Eme heterodimer bound to the scaffold protein SLX4 that carries SLX1 [23,24,25]. The remaining DSB is repaired through homologous recombination (HR)-mediated DSB
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