Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2
Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2
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DOI：
10.1158/0008-5472.can-07-5807
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Ching-Chow
中科院分区：
文献类型：
--
作者：
Lin, Yi-Chu;Lin, Jung-Hsin;Chen, Ching-Chow
他汀类药物是3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，广泛用于控制高胆固醇血症。最近，据报道它们对某些癌症有有益的效果。在这项研究中，我们表明，他汀类药物抑制历史脱乙酰酶（HDAC）的活性，并增加乙酰化组蛋白-H3的积累和p21（WAF/CIP）在人类癌细胞中的表达。计算模型显示他汀类药物的羧酸部分与HDAC 2的催化位点直接相互作用。在随后的酶促测定中，显示洛伐他汀竞争性抑制HDAC 2活性，Ki值为31.6 μ mol/L。Sp1而不是p53位点被发现是他汀类药物的反应元件所示的p21激酶启动子检测。DNA亲和蛋白结合试验和染色质免疫沉淀试验表明HDAC 1/2解离，CBP结合，导致p21启动子Sp1位点组蛋白H3乙酰化。体外细胞增殖和体内肿瘤生长均受到他汀类药物的抑制。这些结果表明，他汀类药物通过废除HDAC活性和启动子组蛋白-H3乙酰化来调节p21表达的新机制。因此，他汀类药物可能作为新的HDAC抑制剂用于癌症治疗和化学预防。
Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the historic deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a K-i value of 31.6 mu mol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention.