Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

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.

Keywords: DNA damage; DNA repair; Epigenetics; HDAC; cancer; histone; phytochemical.

Figure 1

Model of DNA damage signaling, histone acetylation and chromatin remodeling. Recognition and signaling of a DSB is followed by opening of chromatin to repair the break, terminating in chromatin restoration after DNA break repair. HDAC inhibition, as indicated by HDACI, has been shown to affect key steps in this process (as illustrated) by virtue of deacetylating histone and non-histone proteins involved in signaling and repair.

Figure 2

The role of dietary factors in altering histone acetylation and DNA damage signaling.

Figure 3

The differential effect of DNA damaging agents in cancer and normal cells. HDAC inhibitors are known to cause DSBs through chromatin remodeling and oxidative damage due to ROS generation. Normal cells counteract this by check point activation leading to cell cycle arrest; anti-oxidant mechanisms and effective DNA repair whereas cancer cells known to be defective in some of these mechanisms, for e.g. check point kinases and repair genes, fail to repair the DNA damage leading to cell death.