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A more recent version of this article appeared on November 18, 2005
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Papers In Press, published online ahead of print September 26, 2005
J. Biol. Chem, 10.1074/jbc.M505733200
Submitted on May 25, 2005
Revised on August 10, 2005
Accepted on September 26, 2005

Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes

Chang-Shi Chen, Shu-Chuan Weng, Ping-Hui Tseng, Ho-Pi Lin, and Ching-Shih Chen

Department of Medicinal Chemistry, Ohio State University, Columbus, OH 43210-1291

Corresponding Author: chen.844{at}osu.edu

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC-42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, while MS-275 shows only marginal effect at 5 µM. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition, but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific siRNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small-molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt downregulation.


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