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Molecular and Cellular Biology, November 2006, p. 8122-8135, Vol. 26, No. 21
0270-7306/06/$08.00+0 doi:10.1128/MCB.00289-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Manran Liu,1,
Anthony A. Sauve,2
Xuanmao Jiao,1
Xueping Zhang,1
Xiaofang Wu,1
Michael J. Powell,1
Tianle Yang,2
Wei Gu,3
Maria Laura Avantaggiati,4
Nagarajan Pattabiraman,4
Timothy G. Pestell,1
Fang Wang,5
Andrew A. Quong,1
Chenguang Wang,1 and
Richard G. Pestell1*
Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,1 Department of Pharmacology, Weill Medical College, Cornell University, 1300 York Avenue, New York, New York 10021,2 Institute of Cancer Genetics, Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, New York 10032,3 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, D.C. 20057,4 Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 104615
Received 15 February 2006/ Returned for modification 23 March 2006/ Accepted 7 August 2006
The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.
Published ahead of print on 21 August 2006.
M. Fu and M. Liu contributed equally to the manuscript.
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