Abstract
Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies.
Highlights
Genomic instability is a key feature of cancer development, often associated with the acquisition of mutations in oncogenes, tumor suppressor genes, and DNA repair genes [1]
As we learn more about the DNA damage response pathways dysregulated in cancer cells, new combinations of agents are being developed with enhanced therapeutic efficacy [7]
The present review summarizes recent advances in our understanding of histone deacetylase (HDAC) involved in the DNA damage response, and the possible implications for cancer therapy
Summary
Genomic instability is a key feature of cancer development, often associated with the acquisition of mutations in oncogenes, tumor suppressor genes, and DNA repair genes [1]. HDAC inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving ATM [17]. Deacetylation by HDACs stabilized Sae, but VPA inhibited this process [20] Consistent with these observations, a recent study showed that a class III HDAC (SIRT6) positively regulated the repair of double-strand breaks (DSBs) through deacetylation of CtIP [21]. Dietary anticancer compounds modulate drug metabolizing enzymes and scavenge free radicals, under some conditions they have been shown to generate reactive oxygen species (ROS) and cause oxidative DNA damage [31,32] Given this background, the present review summarizes recent advances in our understanding of HDACs involved in the DNA damage response, and the possible implications for cancer therapy. Information regarding HDAC 5, 7, 8 and 11 is currently lacking in terms of a definite role in this mechanism
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