INK4 Family\\---A Promising Target for \lqGene-Regulating Chemoprevention\rq and \lqMolecular-Targeting Prevention\rq of Cancer---

ABSTRACT

Inactivation of the p16INK4a gene is one of the most frequent defects that contribute to oncogenesis in human cancer, since it is a tumor-suppressor gene. Therefore, functional restoration of p16INK4a is one of the most effective methods for cancer prevention. We proposed the concept of ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer, which assumes that transcriptional regulation by drugs on tumor-suppressor genes or functionally similar genes to the tumor-suppressor genes contributes to the prevention of human malignancies. The p16INK4a homologs p15INK4b, p18INK4c and p19INK4d have been recently identified, and these four members constitute the INK4 family of proteins. All directly bind to cyclin D-cyclin dependent kinase (CDK) 4/6 and are therefore specific inhibitors of these complexes. We recently showed that histone deacetylase (HDAC) inhibitors, promising chemopreventive and chemotherapeutical agents, induce p15INK4b and p19INK4d gene expression and cause growth arrest, suggesting that both genes are important molecular targets for HDAC inhibitors. Furthermore, we found that 12-O-tetradecanoylphorbol-13-acetate (TPA), which is widely used as a tumor promoter and protein kinase C activator, promotes human cancer cell growth through the down-regulation of p18INK4c gene expression. This suggests that a mouse two-stage carcinogenesis model using TPA might partially represent the most common human carcinogenesis pathway related to RB. Our results suggest that the INK4 family consists of attractive and promising molecular targets for the ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer.