Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2
Journal
Cancer Research
Journal Volume
68
Journal Issue
7
Pages
2375-2383
Date Issued
2008
Author(s)
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 p21WAF/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 Ki value of 31.6 μmol/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. ?2008 American Association for Cancer Research.
SDGs
Other Subjects
carboxylic acid; cyclin dependent kinase inhibitor 1; DNA; histone deacetylase 1; histone deacetylase 2; hydroxymethylglutaryl coenzyme A reductase inhibitor; luciferase; mevinolin; protein p21; protein p53; acetylation; article; binding affinity; cancer growth; catalysis; cell proliferation; chromatin immunoprecipitation; controlled study; dissociation constant; drug inhibition; enzyme activity; human; human cell; in vivo study; lung carcinoma; priority journal; promoter region; protein expression; protein interaction; Acetylation; Animals; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Female; HCT116 Cells; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Mice, Inbred BALB C; Promoter Regions (Genetics); Repressor Proteins; Xenograft Model Antitumor Assays
Type
journal article