The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation
The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation
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DOI：
10.1093/jn/132.5.1012
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发表时间：
2002-05-01
影响因子：
4.2
通讯作者：
Hodin, RA
中科院分区：
文献类型：
--
作者：
Hinnebusch, BF;Meng, SF;Hodin, RA
短链脂肪酸（SCFA）丁酸是在结肠内通过厌氧菌发酵产生的，并且被认为在结肠癌发生方面具有保护作用。尽管丁酸（C4）被认为是最有效的短链脂肪酸，但结肠腔内还存在多种其他短链脂肪酸。丁酸被认为是通过诱导组蛋白高度乙酰化来发挥其细胞效应的。我们试图确定多种短链脂肪酸对结肠癌细胞生长、分化和凋亡的影响。用生理相关浓度的各种短链脂肪酸处理HT - 29或HCT - 116（野生型和p21缺失型）细胞，通过酸性尿素 - 曲拉通X凝胶电泳和免疫印迹法检测组蛋白乙酰化状态。通过流式细胞术研究生长和凋亡效应，使用瞬时转染和Northern印迹法评估分化效应。丙酸（C3）和戊酸（C5）导致人结肠癌细胞生长停滞和分化。与丁酸相比，它们的作用程度与较低程度的组蛋白高度乙酰化相关。相反，乙酸（C2）和己酸（C6）不会引起组蛋白高度乙酰化，对细胞生长或分化也没有明显影响。短链脂肪酸诱导的分化标记基因肠道碱性磷酸酶（IAP）的反式激活被组蛋白去乙酰化酶（HDAC）阻断，这进一步支持了短链脂肪酸和组蛋白之间的关键联系。丁酸还显著增加凋亡，而所研究的其他短链脂肪酸则没有。短链脂肪酸诱导的生长停滞的特征是p21细胞周期抑制剂表达增加以及细胞周期蛋白B1（CB1）下调。在p21缺失的HCT - 116结肠癌细胞中，短链脂肪酸没有改变增殖速率。这些数据表明，各种短链脂肪酸的抗增殖、凋亡和分化特性与诱导的组蛋白高度乙酰化程度有关。此外，短链脂肪酸介导的结肠癌细胞生长停滞需要p21基因。
The short-chain fatty acid (SCFA) butyrate is produced via anaerobic bacterial fermentation within the colon and is thought to be protective in regard to colon carcinogenesis. Although butyrate (C4) is considered the most potent of the SCFA, a variety of other SCFA also exist in the colonic lumen. Butyrate is thought to exert its cellular effects through the induction of histone hyperacetylation. We sought to determine the effects of a variety of the SCFA on colon carcinoma cell growth, differentiation and apoptosis. HT-29 or HCT-116 (wild-type and p21-deleted) cells were treated with physiologically relevant concentrations of various SCFA, and histone acetylation state was assayed by acid-urea-triton-X gel electrophoresis and immunoblotting. Growth and apoptotic effects were studied by flow cytometry, and differentiation effects were assessed using transient transfections and Northern blotting. Propionate (C3) and valerate (C5) caused growth arrest and differentiation in human colon carcinoma cells. The magnitude of their effects was associated with a lesser degree of histone hyperacetylation compared with butyrate. Acetate (C2) and caproate (C6), in contrast, did not cause histone hyperacetylation and also had no appreciable effects on cell growth or differentiation. SCFA-induced transactivation of the differentiation marker gene, intestinal alkaline phosphatase (IAP), was blocked by histone deacetylase (HDAC), further supporting the critical link between SCFA and histones. Butyrate also significantly increased apoptosis, whereas the other SCFA studied did not. The growth arrest induced by the SCFA was characterized by an increase in the expression of the p21 cell-cycle inhibitor and down-regulation of cyclin B1 (CB1). In p21-deleted HCT-116 colon cancer cells, the SCFA did not alter the rate of proliferation. These data suggest that the anti proliferative, apoptotic and differentiating properties of the various SCFA are linked to the degree of induced histone hyperacetylation. Furthermore, SCFA-mediated growth arrest in colon carcinoma cells requires the p21 gene.