Development of specific prevention against people with high susceptibility for cancer and general carcinogenesis

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1. p27 is a crucial tumor-suppressor gene. Vitamin D3 (VD3) activated p27 via promoter region and repressed cell growth. VD3 stimulated transcription of the p27 by a novel mechanism involving Sp1 and NF-Y, but not the VD3 receptor. These results indicate that we could develop a new drug without side effect such as hypercalcemia mediated by the VD3 receptor.2. Butyrate, a dietay fiber metabolite, activated p21/WAF1 and acted as histone deacetylase (HDAC) inhibitor. We previously reported that butyrate activated p21/WAF1 by Sp1 and Sp3 through Sp1 site of the promoter. Moreover, butyrate activated gadd45 causing cell-cycle arrest and DNA repair. This activation is mediated through Oct-1 box and CCAAT box. p21/WAF1 and gadd45 are regulated by p53. p53 is critical factor in Li-Fraumeni syndrome and is inactivated in a half of malignancies. HDAC inhibitors which activate p21/WAF1 and gadd45 mght be preventive against patient of Li-Fraumeni syndrome or common cancer.3. p16 as well as p53 is a gene inactivated in a half of malignancies. The promoter regions of p16 gene, p15-family genes (p15, p18 and p19) and p53-regulated genes (BAX, DR5, Sian-1 and PUMA) were cloned. We screened drugs activating these genes via these promoter regions and found intersting regulators. These regulators may become novel drugs for prevention of specific cancer.