Mottet D, Pirotte S, Lamour V, Hagedorn M, Javerzat S, Bikfalvi A, Bellahcène A, Verdin E, Castronovo V
Metastasis Research Laboratory, GIGA-Cancer (Center for Experimental Cancer Research), University of Liège, Liège, Belgium.
Oncogene. 2009 Jan 15;28(2):243-56. doi: 10.1038/onc.2008.371. Epub 2008 Oct 13.
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 transcriptional reactivation 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.
癌细胞具有复杂、独特的特征，使其有别于正常细胞，如生长速率增加以及逃避抗增殖信号。对I类和II类组蛋白去乙酰化酶（HDAC）的全面抑制可在体外阻止癌细胞增殖，并且在临床试验中已证明对癌症有效，至少部分是通过p21（WAF1/Cip1）基因的转录重新激活实现的。调控p21（WAF1/Cip1）的HDAC尚未完全明确。利用小干扰RNA，我们发现HDAC4通过Sp1/Sp3结合位点而非p53结合位点参与对p21（WAF1/Cip1）的抑制。HDAC4与Sp1相互作用，在富含Sp1/Sp3结合位点的p21（WAF1/Cip1）近端启动子处结合并降低组蛋白H3的乙酰化，这表明Sp1在HDAC4介导的p21（WAF1/Cip1）抑制中起关键作用。HDAC4沉默介导的p21（WAF1/Cip1）诱导在体外使癌细胞生长停滞，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的新型抗癌疗法的有用靶点。
