Histone Deacetylase Inhibitors ---Promising Agents for \lqGene-Regulating Chemoprevention\rq and \lqMolecular-Targeting Prevention\rq of Cancer---

ABSTRACT

One of the best approaches against cancer is prevention. Inactivation of the p53 or p16INK4a genes has been extensively reported in most human cancer cells. Both p53 and p16INK4a function as tumor suppressors. Therefore, functional restoration of these molecules is considered to be one of the most useful methods for cancer prevention and therapy. We have proposed a concept termed ‘gene-regulating chemoprevention and chemotherapy’ regarding the above pathway. This concept assumes that transcriptional regulation by drugs on tumor-suppressor genes, downstream target genes or functionally similar genes (for example, family genes) of the tumor-suppressor genes would contribute to the prevention of human malignancies. Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation and apoptotic cell death. Previously, we demonstrated that HDAC inhibitors, such as sodium butyrate and trichostatin A (TSA), transcriptionally induce the cyclin-dependent kinase inhibitor p21WAF1/Cip1, a downstream target gene of p53, in a p53-independent manner. Furthermore, we have recently shown that HDAC inhibitors activate Gadd45, another downstream target gene of p53, and p19INK4d, a gene functionally similar to p16INK4a. Our results, taken together with previous findings, suggest that HDAC inhibitors may be one of the most attractive and promising agents for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer.