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.
Department of Pharmacology and Experimental Therapeutics and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Kexin
K
Xu
Hermela
H
Shimelis
Douglas E
DE
Linn
Richeng
R
Jiang
Xi
X
Yang
Feng
F
Sun
Zhiyong
Z
Guo
Hege
H
Chen
Wei
W
Li
Hegang
H
Chen
Xiangtian
X
Kong
Jonathan
J
Melamed
Shengyun
S
Fang
Zhen
Z
Xiao
Timothy D
TD
Veenstra
Yun
Y
Qiu
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