INK4 Family —A promising target for ‘gene-regulating chemoprevention’ and ‘molecular-targeting prevention’ of cancer

Abstract

Inactivation of the p16 INK4a 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 p16 INK4a 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 p16 INK4a homologs p15 INK4b , p18 INK4c and p19 INK4d 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 p15 INK4b and p19 INK4d 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 p18 INK4c 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.

Characterization of the regulation and function of zinc-dependent histone deacetylases during rodent liver regeneration

“…Cyclin dependent kinase inhibitors (CDKIs), which include members of the Cip-Kip and INK4 families, regulate such cell cycle progression (31;32). Moreover, Zn-HDAC inhibition stimulates the transcription of many CDKIs (33-40). Therefore the influence of SAHA on CDKI expression in regenerating liver was examined.…”

“…In contrast, p21 Cip1 , p27 Kip1 , p57 Kip2 , and p18 INK4c expression were not augmented by SAHA (Supplementary Figure 4B-F). Zn-HDAC inhibition has previously been reported to augment the expression of p19 INK4d and other CDKIs (33-40), raising the possibility that PH-induced Zn-HDAC activity might promote normal liver regeneration by suppressing hepatic p19 INK4d expression. Therefore, hepatic p19 INK4d expression was also quantified in untreated mice subjected to PH or sham surgery.…”

Identification of JTP‐70902, a p15INK4b‐inductive compound, as a novel MEK1/2 inhibitor

“…( 10,12 ) These observations suggest that p15 INK4b may function as a replacement for p16 INK4a , and that agents with the ability to induce p15 INK4b may provide new strategies for the prevention or therapy of malignancies, especially against tumors that lack p16 INK4a function. ( 13–16 )…”

“Combination-oriented molecular-targeting prevention” of cancer: a model involving the combination of TRAIL and a DR5 inducer

“…1a) [1][2][3]. In line with this concept, we have shown that chemoprevention can be realized by regulating the expression of a specific gene as a target molecule.…”

“…Many recent reports have elucidated the molecular mechanisms by which various food components prevent carcinogenesis. We have also found that many chemopreventive food components induce the expression of molecules that inhibit carcinogenesis [1][2][3]. We therefore hypothesized that the combination of several components chosen on the basis of their molecular mechanisms would be useful for the prevention of cancer, which we termed ''combination-oriented molecular-targeting prevention'' of cancer.…”