Abstract
Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) family proteins. Gene silencing procedures, in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Depleting NWD1 in PCa cell lines reduces AR levels and suppresses activity of androgen-driven reporter genes. NWD1 knockdown potently suppressed growth of androgen-dependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomic analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, these data suggest a role for tumor-associated over-expression of NWD1 in dysregulation of AR signaling in PCa.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Androgens / pharmacology
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Animals
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Apoptosis
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Blotting, Western
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Cell Proliferation
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Cells, Cultured
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Chromatography, Liquid
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Gene Expression Regulation, Neoplastic*
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HEK293 Cells
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Male
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Mice
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Prostate / metabolism
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Prostate / pathology
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Prostatic Intraepithelial Neoplasia / genetics
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Prostatic Intraepithelial Neoplasia / metabolism
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Prostatic Intraepithelial Neoplasia / pathology
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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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Prostatic Neoplasms, Castration-Resistant / genetics
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Prostatic Neoplasms, Castration-Resistant / metabolism
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Prostatic Neoplasms, Castration-Resistant / pathology
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Proteomics
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Proto-Oncogene Proteins c-ets / genetics
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Proto-Oncogene Proteins c-ets / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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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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Sex-Determining Region Y Protein / genetics
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Sex-Determining Region Y Protein / metabolism
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Signal Transduction*
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Tandem Mass Spectrometry
Substances
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AR protein, human
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Adaptor Proteins, Signal Transducing
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Androgens
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Proto-Oncogene Proteins c-ets
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RNA, Messenger
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Receptors, Androgen
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SPDEF protein, human
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SRY protein, human
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Sex-Determining Region Y Protein