HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism
HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism
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DOI：
10.1038/onc.2008.371
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发表时间：
2009-01-01
期刊：
影响因子：
8
通讯作者：
Castronovo, V.
中科院分区：
文献类型：
--
作者：
Mottet, D.;Pirotte, S.;Castronovo, V.
癌细胞具有将其与正常细胞区分开的复杂、独特的特征，例如增加的生长速率和逃避抗增殖信号。I类和II类组蛋白去乙酰化酶（HDAC）的整体抑制在体外停止癌细胞增殖，并且在临床试验中已经证明对癌症有效，至少部分地通过p21（WAF 1/Cip 1）基因的转录激活。调节p21（WAF 1/Cip1）的HDAC尚未完全确定。使用小干扰RNA，我们发现HDAC 4通过Sp1/Sp3-而不是p53-结合位点参与p21（WAF 1/Cip1）的抑制。HDAC4与Sp1相互作用，结合并减少组蛋白H3在Sp1/Sp3结合位点丰富的p21（WAF 1/Cip1）近端启动子处的乙酰化，表明Sp1在HDAC4介导的p21（WAF 1/Cip1）抑制中起关键作用。通过HDAC 4沉默介导的p21（WAF 1/Cip1）诱导在体外抑制癌细胞生长，并在体内人胶质母细胞瘤模型中抑制肿瘤生长。因此，HDAC4可能是基于选择性抑制特定HDAC的新抗癌疗法的有用靶标。
Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptionalreac tivation of the p21(WAF1/Cip1) gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.