Sterol regulatory element-binding protein-1c represses the transactivation of androgen receptor and androgen-dependent growth of prostatic cells.
Sterol regulatory element-binding protein-1c (SREBP-1c) is a basic helix-loop-helix transcription factor that plays an important role in lipid homeostasis. Here, we show that SREBP-1c regulates androgen receptor (AR) transactivation through direct interaction with AR and represses androgen-dependent growth of prostatic cells. Transient transfection studies show that SREBP-1c specifically inhibits the ... transactivation of AR. Chromatin immunoprecipitation assays reveal that SREBP-1c is recruited with AR onto the endogenous AR target promoter. Moreover, adenovirus-mediated overexpression of SREBP-1c decreases the mRNA level of the prostate-specific antigen gene, an endogenous target gene of AR, supporting SREBP-1c modulation of AR transactivation. In vivo and in vitro protein interaction assays show that SREBP-1c directly interacts with AR through the activation function-1 domain of AR. In addition, transfection studies and glutathione S-transferase pull-down competition experiments reveal that the SREBP-1c-mediated repression of AR transactivation is accomplished through competition with certain AR coactivators for AR interaction. The SREBP-1c-mediated inhibition of AR transactivation also involves the recruitment of histone deacetylase 1. Finally, adenovirus-mediated overexpression of SREBP-1c inhibits androgen-induced proliferation of prostatic cells in vitro and in vivo, and small interfering RNA-mediated down-regulation of SREBP-1 enhances androgen-induced proliferation of prostatic cells as well as the transactivation of AR. Taken together, these results suggest that SREBP-1c acts as an AR corepressor and may play an important role in the regulation of AR-dependent prostatic cell growth.
Mesh Terms:
Androgens, Animals, Cell Line, Tumor, Cell Proliferation, Histone Deacetylase 1, Histone Deacetylases, Male, Mice, Promoter Regions, Genetic, Prostate, Protein Binding, Receptors, Androgen, Repressor Proteins, Sterol Regulatory Element Binding Protein 1, Transcription, Genetic, Transcriptional Activation, Xenograft Model Antitumor Assays
Androgens, Animals, Cell Line, Tumor, Cell Proliferation, Histone Deacetylase 1, Histone Deacetylases, Male, Mice, Promoter Regions, Genetic, Prostate, Protein Binding, Receptors, Androgen, Repressor Proteins, Sterol Regulatory Element Binding Protein 1, Transcription, Genetic, Transcriptional Activation, Xenograft Model Antitumor Assays
Mol. Cancer Res.
Date: Feb. 01, 2008
PubMed ID: 18245227
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