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  • Title: Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis.
    Author: Habold C, Poehlmann A, Bajbouj K, Hartig R, Korkmaz KS, Roessner A, Schneider-Stock R.
    Journal: J Cell Mol Med; 2008 Apr; 12(2):607-21. PubMed ID: 18419600.
    Abstract:
    Many studies aim at improving therapeutic efficacy by combining strategies with oxidative stress-inducing drugs and histone deacetylase (HDAC) inhibitors in colorectal cancer. As p53 and p21(WAF1) are essential in oxidative stress-induced DNA damage, we investigated epigenetic regulation of p21(WAF1) promoter. Firstly, HCT116 p53(+)/(+) and p53(-)/(-) colorectal cancer cells were treated with H(2)O(2) for 6 hrs and 24 hrs (early/late response). Chromatin immunoprecipitation revealed transcriptional transactivation of p21(WAF1) in HCT116 p53(+)/(+) cells as shown by increased binding of p53 and acetylated H4 around two p21(WAF1) promoter sites, the responsible element (RE) and the Sp1 site, while both proteins bound preferentially on the RE. Interestingly, H3 was not involved, suggesting H4-specific transactivation of the p21(WAF1) promoter. H(2)O(2) addition resulted in G(2)/M arrest of both HCT116 cell lines without significant cell death. To investigate whether a HDAC inhibitor strengthens G(2)/M arrest, we pretreated cells with Trichostatin A (TSA). In HCT116 p53(+)/(+) cells, we found (i) remarkably increased acetylated H4 around both p21(WAF1) promoter regions, especially at the Sp1 site; (ii) increased acetylation of p53 at lysines 320 and 382;(iii) displacement of HDAC1 from the Sp1 site, thus inhibiting its repression effect and increasing p53 binding.p53 seems to trigger H4-acetylation around the p21(WAF1) promoter because there was nearly no H4 acetylation in HCT116 p53(-)/(-) cells. For the first time we show that there is a time-dependent TSA mode of action with increased p53-dependent histone H4 acetylation at the p21(WAF1) promoter in early response, and decreased acetylation in late response. Reduced p53-triggered transactivation of p21(WAF1) in late response allows cells to re-enter cell cycle, and TSA causes p53 to simultaneously induce apoptosis.
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