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.
Suh
Ji Ho
JH
Hormone Research Center, Chonnam National University, Gwangju, Republic of Korea.
Gong
Eun-Yeung
EY
Kim
Jae Bum
JB
Lee
In-Kyu
IK
Choi
Hueng-Sik
HS
Lee
Keesook
K
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D011944:Receptors, Androgen; D012097:Repressor Proteins; D051780:Sterol Regulatory Element Binding Protein 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases