Abstract
Androgen receptor (AR)-mediated transcription is modulated by interaction with coregulatory proteins. We demonstrate that the unconventional prefoldin RPB5 interactor (URI) is a new regulator of AR transcription and is critical for antagonist (bicalutamide) action. URI is phosphorylated upon androgen treatment, suggesting communication between the URI and AR signaling pathways. Whereas depletion of URI enhances AR-mediated gene transcription, overexpression of URI suppresses AR transcriptional activation and anchorage-independent prostate cancer cell growth. Repression of AR-mediated transcription is achieved, in part, by URI binding and regulation of androgen receptor trapped clone 27 (Art-27), a previously characterized AR corepressor. Consistent with this idea, genome-wide expression profiling in prostate cancer cells upon depletion of URI or Art-27 reveals substantially overlapping patterns of gene expression. Further, depletion of URI increases the expression of the AR target gene NKX-3.1, decreases the recruitment of Art-27, and increases AR occupancy at the NKX-3.1 promoter. While Art-27 can bind AR directly, URI is bound to chromatin prior to hormone-dependent recruitment of AR, suggesting a role for URI in modulating AR recruitment to target genes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Antagonists / pharmacology
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Anilides / pharmacology
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Blotting, Western
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin / metabolism
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Chromatin Immunoprecipitation
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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HEK293 Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Metribolone / pharmacology
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Molecular Chaperones
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nitriles / pharmacology
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Oligonucleotide Array Sequence Analysis
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Phosphorylation / drug effects
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Prostatic Neoplasms / embryology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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Protein Binding
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RNA Interference
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Repressor Proteins
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Reverse Transcriptase Polymerase Chain Reaction
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Tosyl Compounds / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics*
Substances
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Androgen Antagonists
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Anilides
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Cell Cycle Proteins
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Chromatin
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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NKX3-1 protein, human
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Neoplasm Proteins
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Nitriles
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Receptors, Androgen
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Repressor Proteins
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Tosyl Compounds
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Transcription Factors
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URI1 protein, human
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UXT protein, human
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Metribolone
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bicalutamide