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Updated: Mar 14, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their
John A Halsall1, Bryan M Turner2
1Chromatin and Gene Expression Group, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Abstract:
Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors 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 signaling 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. Also see the video abstract here.
Insights
Human cells possess a defense mechanism against histone deacetylase inhibitors (HDACi), mitigating their toxic effects. Cancers may be sensitive to HDACi if this resistance response is impaired by mutations.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Histone deacetylase inhibitors (HDACi) show promise in cancer therapy but have mixed results in solid tumors.
- The mechanisms underlying differential cancer cell sensitivity and normal cell tolerance to HDACi are not fully understood.
Purpose of the Study:
- To investigate the cellular response to HDACi that confers tolerance.
- To propose a hypothetical signaling system mediating this resistance.
- To explore the evolutionary basis of HDACi resistance and its implications for cancer treatment.
Main Methods:
- Review of recent findings on cellular responses to HDACi.
- Hypothetical modeling of a signaling system for resistance.
- Analysis of evolutionary pressures and cancer mutations.
Main Results:
- Human cells exhibit a coordinated transcriptional response to HDACi, mitigating toxicity.
- A hypothetical signaling pathway is proposed to mediate this resistance.
- Environmental exposure to HDACi likely drove the evolution of this resistance response in human cells.
Conclusions:
- Cancer cell sensitivity to HDACi may be linked to defects in the cellular resistance response.
- Identifying mutations compromising this response could guide targeted HDACi therapy to susceptible cancers.
- Understanding the resistance mechanism is crucial for optimizing HDACi efficacy in oncology.
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