Spurling Colleen C, Godman Cassandra A, Noonan Emily J, Rasmussen Theodore P, Rosenberg Daniel W, Giardina Charles
Department of Molecular & Cell Biology, University of Connecticut, Storrs, Connecticut, USA.
Mol Carcinog. 2008 Feb;47(2):137-47. doi: 10.1002/mc.20373.
An immunohistochemical analysis of human colorectal adenocarcinomas showed that cancer cells express widely varying levels of HDAC3. The SW480 colon cancer cell line was found to express high levels of HDAC3 compared to other colon cancer cell lines. p21 was poorly induced in SW480 cells relative to the lower HDAC3-expressing HT-29 cells. RNAi-induced reduction of HDAC3 in SW480 cells increased their constitutive, butyrate-, TSA-, and TNF-alpha-induced expression of p21, but did not cause all the gene expression changes induced upon general histone deacetylase (HDAC) inhibition. SW480 cells with lower HDAC3 expression appeared to be poised for gene expression responses with increased histone H4-K12 acetylation, but not K5, K8, or K16 acetylation. Even though p21 was readily activated in HT29 cells, HDAC3 siRNA nonetheless stimulated p21 expression in these cells to a greater degree than HDAC1 and HDAC2 siRNA. SW480 cells with lower HDAC3 levels displayed an enhanced cell cycle arrest and growth inhibition by butyrate, but without changes in apoptosis or sensitivity to chemotherapeutic agents. As reported for other colon cancer cell lines, butyrate induced the rapid downregulation of the secretory cell differentiation markers mucin 2 and intestinal trefoil factor in SW480 cells. Interestingly, selective HDAC3 inhibition was sufficient to downregulate these genes. Our data support a central role for HDAC3 in regulating the cell proliferation and differentiation of colon cancer cells and suggest a potential mechanism by which colon cancers may become resistant to luminal butyrate.
对人类结肠腺癌的免疫组织化学分析表明，癌细胞表达的HDAC3水平差异很大。与其他结肠癌细胞系相比，SW480结肠癌细胞系被发现表达高水平的HDAC3。相对于低表达HDAC3的HT - 29细胞，p21在SW480细胞中诱导较差。RNA干扰诱导SW480细胞中HDAC3的减少增加了其组成性、丁酸盐、曲古抑菌素A和肿瘤坏死因子-α诱导的p21表达，但并未引起一般组蛋白去乙酰化酶（HDAC）抑制所诱导的所有基因表达变化。HDAC3表达较低的SW480细胞似乎已准备好对基因表达作出反应，其组蛋白H4 - K12乙酰化增加，但K5、K8或K16乙酰化未增加。尽管p21在HT29细胞中很容易被激活，但HDAC3 siRNA在这些细胞中对p21表达的刺激程度仍大于HDAC1和HDAC2 siRNA。HDAC3水平较低的SW480细胞表现出丁酸盐增强的细胞周期停滞和生长抑制，但细胞凋亡或对化疗药物的敏感性没有变化。正如对其他结肠癌细胞系的报道一样，丁酸盐诱导SW480细胞中分泌细胞分化标志物粘蛋白2和肠三叶因子的快速下调。有趣的是，选择性HDAC3抑制足以下调这些基因。我们的数据支持HDAC3在调节结肠癌细胞的细胞增殖和分化中起核心作用，并提示结肠癌可能对肠腔丁酸盐产生抗性的潜在机制。
