HDAC3 overexpression and colon cancer cell proliferation and differentiation
HDAC3 overexpression and colon cancer cell proliferation and differentiation
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DOI：
10.1002/mc.20373
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发表时间：
2008-02-01
影响因子：
4.6
通讯作者：
Giardina, Charles
中科院分区：
文献类型：
--
作者：
Spurling, Colleen C.;Godman, Cassandra A.;Giardina, Charles
对人类结直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 HDAC3 表达较低的 HT-29 细胞，p21 在 SW480 细胞中的诱导较差。 SW480 细胞中 HDAC3 的 RNAi 减少增加了其组成型、丁酸、TSA 和 TNF-α 诱导的 p21 表达，但并没有引起一般组蛋白脱乙酰酶 (HDAC) 抑制诱导的所有基因表达变化。 HDAC3 表达较低的 SW480 细胞似乎准备好进行基因表达反应，组蛋白 H4-K12 乙酰化增加，但 K5、K8 或 K16 乙酰化则不然。尽管 p21 在 HT29 细胞中很容易被激活，但 HDAC3 siRNA 仍然比 HDAC1 和 HDAC2 siRNA 更大程度地刺激这些细胞中的 p21 表达。 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作用，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，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的核心作用，并提出结肠癌可能对管腔丁酸盐产生耐药性的潜在机制。 (C) 2007 Wiley-Liss, Inc.
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-incluced 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. (C) 2007 Wiley-Liss, Inc.