Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2
- 1 April 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (7), 2375-2383
- https://doi.org/10.1158/0008-5472.can-07-5807
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. [Cancer Res 2008;68(7):2375–83]Other Versions
This publication has 44 references indexed in Scilit:
- Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genesGenome Research, 2007
- Phosphorylation of CBP by IKKα Promotes Cell Growth by Switching the Binding Preference of CBP from p53 to NF-κBMolecular Cell, 2007
- Anticancer activities of histone deacetylase inhibitorsNature Reviews Drug Discovery, 2006
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- Statins and cancer preventionNature Reviews Cancer, 2005
- Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancerNature Genetics, 2005
- PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculationsNucleic Acids Research, 2004
- HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosisLeukemia, 2002
- CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choiceNucleic Acids Research, 1994
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993