title: Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.
abstract: 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 histone 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 micromol/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.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Lin
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Chou
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Chang
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Yeh
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D005260:Female; D045325:HCT116 Cells; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012097:Repressor Proteins; C012589:trichostatin A; D000077337:Vorinostat; C110550:HDAC1 protein, human; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases