Histone deacetylase 3 (HDAC3) and other class IHDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer
Histone deacetylase 3 (HDAC3) and other class IHDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer
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DOI：
10.1074/jbc.m510023200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Mariadason, JM
中科院分区：
文献类型：
--
作者：
Wilson, AJ;Byun, DS;Mariadason, JM
组蛋白脱乙酰酶(HDAC)抑制剂在体外诱导结肠癌细胞株的生长停滞、分化和凋亡，并在临床试验中证明了抗癌效果。虽然HDAC1和-2在HDAC抑制反应的调节成分中的作用已有报道，但HDAC3的作用尚不清楚。在这里，我们证明了HDAC3在人类结肠肿瘤和来自Apc1638(N/+)小鼠的十二指肠腺瘤中的蛋白表达增加。在正常肠组织中，HDAC3在增殖的隐窝细胞中表达最强。在结肠癌细胞系中，沉默HDAC3的表达导致生长抑制，细胞存活率下降，并增加细胞凋亡率。HDAC2也有类似的效果，HDAC1的影响程度较小。HDAC3沉默还选择性地诱导碱性磷酸酶的表达，碱性磷酸酶是结肠细胞成熟的标志。在影响细胞生长的同时，HDAC3和其他I类HDAC的过表达以Sp1/Sp3依赖的方式抑制基础转录和丁酸诱导的p21转录，而沉默HDAC3则刺激p21启动子的活性和表达。然而，沉默单个I类HDAC所引起的影响的幅度明显小于HDAC抑制剂所引起的影响。这些发现确认HDAC3是一个在人类结肠癌中被解除调控的基因，并且是一种新的结肠细胞成熟和p21表达的调节因子。这些发现还表明，多个I类HDAC参与抑制p21，并提示HDAC抑制剂诱导的生长抑制和凋亡效应可能是通过抑制多个HDAC介导的。
Inhibitors of histone deacetylases (HDACs) induce growth arrest, differentiation, and apoptosis of colon cancer cell lines in vitro and have demonstrated anti-cancer efficacy in clinical trials. Whereas a role for HDAC1 and -2 in mediating components of the HDAC inhibitor response has been reported, the role of HDAC3 is unknown. Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice. HDAC3 was also maximally expressed in proliferating crypt cells in normal intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increasedapoptosis. SimilareffectswereobservedforHDAC2and, toa lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, amarker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 and other Class I HDACs inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression. However, the magnitude of the effects elicited by silencing of individual Class I HDACs was significantly less than that induced by HDAC inhibitors. These findings identify HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression. These findings also demonstrate that multiple Class I HDACs are involved in repressing p21 and suggest that the growthinhibitory and apoptotic effects induced byHDACinhibitors are probably mediated through the inhibition of multiple HDACs.