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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.

Hormonal Control of Androgen Receptor Function through SIRT1

Maofu Fu,^1, 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. Pestell^1*

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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