【摘 要】
：
Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors which have been broadly used for the control of hypercholesterolemia.Recently, they were reported to have beneficial effects on certain
【机 构】
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Research Center for Applied Sciences and Institute of Biomedical Sciences Academia Sinica/School of
【出 处】
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BIT‘s2nd Annual World Cancer Congess-2009 (2009第二届癌症大会)
论文部分内容阅读
Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors which have been broadly used for the control of hypercholesterolemia.Recently, they were reported to have beneficial effects on certain cancers.In our study, we showed that statins inhibited the histone deacetylase (HDAC) activity.Multiple sequence alignment, homology modeling, and docking of statins onto the zinc-containing active site of HDAC showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC.In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a Ki value of 31.6μM.We also showed that Sp1 but not p53 sites were found to be the statins-responsive element, as shown by p21 luciferase-promoter assays.Statins also increased the accumulation of acetylated histone-H3 and the expression of p21WAF/CIP in human cancer cells.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 may be used as HDAC inhibitors for cancer therapy and chemoprevention.
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