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
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Mol Cell Biol. 2006 Nov;26(21):8122-35. doi: 10.1128/MCB.00289-06. Epub 2006 Aug 21.
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.
烟酰胺腺嘌呤二核苷酸（NAD）依赖性组蛋白去乙酰化酶Sir2在将细胞代谢与基因沉默及衰老联系起来的过程中发挥着关键作用。雄激素受体（AR）是一种受配体调节的模块化核受体，可调控前列腺癌细胞的增殖、分化以及对包括二氢睾酮（DHT）在内的雄激素作出反应时的细胞凋亡。在此，SIRT1拮抗剂可诱导内源性AR表达并增强DHT介导的AR表达。SIRT1在一个保守的赖氨酸基序处与AR结合并使其去乙酰化。人SIRT1（hSIRT1）对DHT诱导的AR信号传导的抑制作用需要hSIRT1的NAD依赖性催化功能以及被SIRT1去乙酰化的AR赖氨酸残基。SIRT1抑制了共激活因子诱导的AR氨基末端和羧基末端之间的相互作用。SIRT1还可阻断DHT诱导的前列腺癌细胞非接触依赖性生长，这在作为人类前列腺癌进展关键决定因素的AR与沉默调节蛋白之间建立了直接的功能联系。
