Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

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Colleges, School and Institutes


Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumours have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi-induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signalling system that could trigger and mediate this response. To account for the existence of such a
response, we note that HDACi of various chemical types, are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers.


Original languageEnglish
Pages (from-to)1102–1110
Issue number11
Early online date22 Sep 2016
Publication statusPublished - 26 Oct 2016


  • cancer , chromatin , deacetylase , evolution , histone modification , epigenetic drugs