The histone deacetylase inhibitor butyrate downregulates cyclin B1 gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells
The histone deacetylase inhibitor butyrate downregulates cyclin B1 gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells
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DOI：
10.1152/ajpgi.00575.2004
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发表时间：
2005-10-01
影响因子：
4.5
通讯作者：
Hodin, RA
中科院分区：
文献类型：
--
作者：
Archer, SY;Johnson, J;Hodin, RA
组蛋白脱乙酰酶(HDAC)抑制剂有望用于多种人类癌症的治疗，但其确切的作用机制尚未阐明。我们研究了HDAC抑制剂丁酸盐对结肠癌细胞的影响，重点是它对细胞周期促进因子Cyclin B-1的影响。在HT-29细胞中，丁酸钠介导的生长抑制与细胞周期蛋白B1的mRNA水平显著降低有关。细胞周期蛋白B1的下降是以延迟的方式发生的(在24小时)，并被蛋白质合成抑制剂同时处理完全阻断，并且似乎依赖于转录的变化。Cyclin B1的抑制与结肠癌细胞的分化过程有关，而不仅仅是与生长停滞有关。丁酸抑制细胞周期蛋白B1的机制需要延长组蛋白的超乙酰化，并且至少部分依赖于p21的表达。事实上，p21/WAF-1似乎直接抑制最小的细胞周期蛋白B-1启动子(-90bp)，这一过程可以由p21蛋白的氨基末端部分介导。这些发现突出了HDAC抑制剂调节其对人类癌细胞有益作用的关键分子机制。
Histone deacetylase (HDAC) inhibitors are showing promise as treatment for a variety of human cancers, but their precise mechanism of action has not been elucidated. We examined the effects of the HDAC inhibitor butyrate on colon cancer cells, focusing on its effect on the cell cycle promoter cyclin B-1. In HT-29 cells, sodium butyrate-mediated growth inhibition is associated with a marked decrease in cyclin B1 mRNA levels. The decrease in cyclin B1 occurred in a delayed fashion ( at 24 h), is completely blocked by concomitant treatment with protein synthesis inhibitors, and appears to be dependent on changes in transcription. Cyclin B1 repression is linked to the differentiation process in colon cancer cells, not merely with growth arrest. The mechanism of cyclin B1 repression by butyrate requires prolonged histone hyperacetylation and is at least partly dependent on p21 expression. In fact, p21/WAF-1 appears to directly repress a minimal cyclin B-1 promoter ( - 90 bp), a process that can be mediated by the amino-terminal portion of the p21 protein. These findings highlight key molecular mechanisms by which HDAC inhibitors mediate their beneficial effects on human cancer cells.