Abstract
Androgen receptor (AR) is a member of the nuclear receptor family of transcription factors. Upon binding to androgens, AR becomes transcriptionally active to regulate the expression of target genes that harbor androgen response elements (AREs) in their promoters and/or enhancers. AR is essential for the growth and survival of prostate cancer cells and is therefore a target for current and next-generation therapeutic modalities against prostate cancer. Pathophysiologically relevant protein-protein interaction networks involving AR are, however, poorly understood. In this study, we identified the protein FUsed/Translocated in LipoSarcoma (FUS/TLS) as an AR-interacting protein by co-immunoprecipitation of endogenous proteins in LNCaP human prostate cancer cells. The hormonal response of FUS expression in LNCaP cells was shown to resemble that of other AR co-activators. FUS displayed a strong intrinsic transactivation capacity in prostate cancer cells when tethered to basal promoters using the GAL4 system. Chromatin immunoprecipitation experiments showed that FUS was recruited to ARE III of the enhancer region of the PSA gene. Data from ectopic overexpression and “knock-down” approaches demonstrated that AR transcriptional activity was enhanced by FUS. Depletion of FUS reduced androgen-dependent proliferation of LNCaP cells. Thus, FUS is a novel co-activator of AR in prostate cancer cells.
Highlights
Androgen receptor (AR) is required for the survival and growth of prostate cancer cells
The lysates were immunoprecipitated with anti-AR antibody and samples were subjected to multidimensional protein identification technology (MudPIT) [8]
Having demonstrated a transactivation capacity of FUsed in Sarcoma (FUS) that was independent of the promoter in prostate cancer cells as described above, we evaluated the involvement of FUS in AR transcriptional activity at target genes
Summary
Androgen receptor (AR) is required for the survival and growth of prostate cancer cells. Continued efforts to develop drugs would benefit from improved understanding of the protein-protein interaction networks involving the AR. To this end, we employed a proteomic approach and identified novel endogenous AR interaction partners in prostate cancer cells that include members of a group of proteins called FET/TET. We employed a proteomic approach and identified novel endogenous AR interaction partners in prostate cancer cells that include members of a group of proteins called FET/TET This family of proteins includes: FUsed in Sarcoma (FUS)/Translocated in LipoSarcoma (TLS), EWig’s Sarcoma protein (EWS), and the TATA binding Protein-Associated Factor, TAF15
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