Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line.

Genistein is the most abundant isoflavone of soybeans and has been shown to cause growth arrest in various human cancer cell lines. However, the precise mechanism for this is still unclear. We report here that the growth arrest and DNA damage-inducible gene 45 (gadd45) gene is induced by genistein via its promoter in a DU145 human prostate cancer cell line. The binding of transcription factor nuclear factor-Y to the CCAAT site of the gadd45 promoter appears to be important for this activation by genistein.

p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y.

Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.

15-Deoxy-Delta(12,14)-prostaglandin J2 induces apoptosis through activation of the CHOP gene in HeLa cells.

Cyclopentenone prostaglandins (PGs) of the J series, which are produced by dehydration of PGD(2), have been reported to induce apoptosis in various cell lines. One of these cyclopentenone PGs, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)), is the most potent inducer of apoptosis in the series, but the signaling pathways by which it induces apoptosis are poorly understood. We recently reported that cyclopentenone PGs accumulate in the endoplasmic reticulum (ER) and it has been shown that the transcription factor CHOP is induced by ER-stresses and elicits apoptosis. In the present study we demonstrated that 15-d-PGJ(2) induces CHOP mRNA/protein in HeLa cells via activation of the conserved regions in the CHOP promoter. Using several mutants of the CHOP promoter fragments, we found that two regions, CCAAT/enhancer-binding protein (C/EBP) site at -313 and ER-stress element (ERSE) at -93, are involved in activation of the CHOP gene by 15-d-PGJ(2). These results suggest that 15-d-PGJ(2) activates the CHOP promoter in two distinct pathways that could induce apoptosis of HeLa cells.

Histone deacetylase inhibitors -Promising agents for 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer-.

One of the best approaches against cancer is prevention. Inactivation of the p53 or p16(INK4a) genes has been extensively reported in most human cancer cells. Both p53 and p16(INK4a) 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 p21(WAF1/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 p19(INK4d), a gene functionally similar to p16(INK4a). 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.