Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination.
The androgen receptor (AR) plays a critical role in prostate cancer. We have identified a ubiquitin E3 ligase, RNF6, as an AR-associated protein in a proteomic screen. RNF6 induces AR ubiquitination and promotes AR transcriptional activity. Specific knockdown of RNF6 or mutation of RNF6-induced ubiquitination acceptor sites on AR selectively alters expression of a subset of AR target genes and diminishes recruitment of AR and its coactivators to androgen-responsive elements present in the regulatory region of these genes. Furthermore, RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. Our data suggest that RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity through modulating cofactor recruitment.
Xu
Kexin
K
Department of Pharmacology and Experimental Therapeutics and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Shimelis
Hermela
H
Linn
Douglas E
DE
Jiang
Richeng
R
Yang
Xi
X
Sun
Feng
F
Guo
Zhiyong
Z
Chen
Hege
H
Li
Wei
W
Chen
Hegang
H
Kong
Xiangtian
X
Melamed
Jonathan
J
Fang
Shengyun
S
Xiao
Zhen
Z
Veenstra
Timothy D
TD
Qiu
Yun
Y
D000595:Amino Acid Sequence; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009376:Neoplasms, Hormone-Dependent; D011470:Prostatic Hyperplasia; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D054875:Ubiquitination
C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C119753:RNF6 protein, human; D011944:Receptors, Androgen