Hormonal control of androgen receptor function through SIRT1 |
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Authors: | Fu Maofu Liu Manran Sauve Anthony A Jiao Xuanmao Zhang Xueping Wu Xiaofang Powell Michael J Yang Tianle Gu Wei Avantaggiati Maria Laura Pattabiraman Nagarajan Pestell Timothy G Wang Fang Quong Andrew A Wang Chenguang Pestell Richard G |
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Institution: | Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. |
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Abstract: | 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. |
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