Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Androgens / pharmacology
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Animals
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Humans
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Immunoenzyme Techniques
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Kidney / cytology
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Kidney / metabolism
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Male
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Molecular Sequence Data
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Neoplasms, Hormone-Dependent
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Prostatic Hyperplasia
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Transcription, Genetic*
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Ubiquitination*
Substances
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AR protein, human
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Androgens
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DNA-Binding Proteins
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RNA, Messenger
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RNF6 protein, human
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Receptors, Androgen