Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2

Yi-Chu Lin,Yu-Fan Chang,Jung-Hsin Lin,Ching-Chow Chen,Shu-Hao Yeh,Chia-Wei Chou

doi: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 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.

Highlights

Statins can reduce serum cholesterol levels by competitively inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of mevalonate
The extent of histone-H3 acetylation induced by 30 Amol/L lovastatin is comparable with that of 0.5 Amol/L trichostatin A (TSA) or 5 mmol/L vaproic acid (VPA)
The protein levels of HDAC1, HDAC2, and HDAC3 were not changed after statins or TSA treatment (Fig. 1D), demonstrating that inhibition of histone deacetylase (HDAC) activity, but not HDAC expression, is responsible for the accumulation of acetylated histone-H3 after statins treatment

Summary

Introduction

Statins can reduce serum cholesterol levels by competitively inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of mevalonate (the fatty acid intermediate in cholesterol biosynthesis). This effect contributes to their decrease in the incidence of cardiovascular and cerebrovascular disorders and their remarkable prevention of cardiovascular disease By inhibiting the biosynthesis of mevalonate, statins inhibit the formation of downstream lipid isoprenoid intermediates, such as farnesyl PPi (FPP) and geranylgeranyl PPi (GGPP). The isoprenoids are lipid moieties that are added to various proteins, including Ras, Rho, and Rac of small G proteins during posttranslational modification (prenylation), and anchor these proteins to the cell membrane [2]. Phone: 886-2-23123456, ext. 8321; Fax: 886-2-23947833; E-mail: chingchowchen@ ntu.edu.tw

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