Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis.
Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis.
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DOI：
10.1111/j.1582-4934.2007.00136.x
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发表时间：
2008-04
影响因子：
5.3
通讯作者：
Schneider-Stock R
中科院分区：
文献类型：
--
作者：
Habold C;Poehlmann A;Bajbouj K;Hartig R;Korkmaz KS;Roessner A;Schneider-Stock R
许多研究旨在通过结合氧化应激诱导药物和组蛋白去乙酰化酶（HDAC）抑制剂的策略来提高结直肠癌的治疗效果。由于p53和p21 WAF 1在氧化应激诱导的DNA损伤中是必不可少的，我们研究了p21 WAF 1启动子的表观遗传调控。首先，用H2 O2处理HCT 116 p53+/+和p53−/−结肠直肠癌细胞6小时和24小时（早期/晚期反应）。染色质免疫沉淀显示p21 WAF 1在HCT 116 p53+/+细胞中的转录反式激活，如通过增加p53和乙酰化H4在两个p21 WAF 1启动子位点（责任元件（RE）和Sp1位点）周围的结合所示，而这两种蛋白质优先结合在RE上。有趣的是，H3没有参与，表明H4特异性的p21 WAF 1启动子的反式激活。H2 O2的加入导致两种HCT 116细胞系的G2/M期阻滞，而没有显著的细胞死亡。为了研究HDAC抑制剂是否增强G2/M期阻滞，我们用曲古抑菌素A（TSA）预处理细胞。在HCT 116 p53+/+细胞中，我们发现：（i）p21 WAF 1启动子区周围的乙酰化H4显著增加，尤其是在Sp1位点;（iii）HDAC 1从Sp1位点的置换，p53似乎触发了p21 WAF 1启动子周围的H4-乙酰化，因为在HCT 116 p53−/- 细胞。我们第一次表明，有一个时间依赖性TSA的行动模式与增加p53依赖性组蛋白H4乙酰化的p21 WAF 1启动子在早期的反应，并减少乙酰化在后期的反应。在晚期应答中减少p53触发的p21 WAF 1的反式激活允许细胞重新进入细胞周期，并且TSA导致p53同时诱导凋亡。
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 p21WAF1 are essential in oxidative stress-induced DNA damage, we investigated epigenetic regulation of p21WAF1 promoter. Firstly, HCT116 p53+/+ and p53−/− colorectal cancer cells were treated with H2O2 for 6 hrs and 24 hrs (early/late response). Chromatin immunoprecipitation revealed transcriptional transactivation of p21WAF1 in HCT116 p53+/+ cells as shown by increased binding of p53 and acetylated H4 around two p21WAF1 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 p21WAF1 promoter. H2O2 addition resulted in G2/M arrest of both HCT116 cell lines without significant cell death. To investigate whether a HDAC inhibitor strengthens G2/M arrest, we pretreated cells with Trichostatin A (TSA). In HCT116 p53+/+ cells, we found (i) remarkably increased acetylated H4 around both p21WAF1 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 p21WAF1 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 p21WAF1 promoter in early response, and decreased acetylation in late response. Reduced p53-triggered transactivation of p21WAF1 in late response allows cells to re-enter cell cycle, and TSA causes p53 to simultaneously induce apoptosis.
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影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
3.1
作者：
Berthiaume, M;Boufaied, N;Gaudreau, L
通讯作者：
Gaudreau, L
影响因子：
11.4
作者：
Ito, A;Kawaguchi, Y;Yao, TP
通讯作者：
Yao, TP
影响因子：
5.3
作者：
Niculescu, AB;Chen, XB;Reed, SI
通讯作者：
Reed, SI