Hormonal control of androgen receptor function through SIRT1.
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.
Fu
Maofu
M
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Liu
Manran
M
Sauve
Anthony A
AA
Jiao
Xuanmao
X
Zhang
Xueping
X
Wu
Xiaofang
X
Powell
Michael J
MJ
Yang
Tianle
T
Gu
Wei
W
Avantaggiati
Maria Laura
ML
Pattabiraman
Nagarajan
N
Pestell
Timothy G
TG
Wang
Fang
F
Quong
Andrew A
AA
Wang
Chenguang
C
Pestell
Richard G
RG
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D013196:Dihydrotestosterone; D051548:Histone Acetyltransferases; D008239:Lysine; D010455:Peptides; D011944:Receptors, Androgen; D056564:Sirtuin 1; D037761:Sirtuins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C447939:SIRT1 protein, human