Coactivator selective regulation of androgen receptor activity

Department of Molecular and Cellular Biology, Baylor College of Medicine, M130, One Baylor Plaza, Houston, TX 77030, United States.
Steroids (Impact Factor: 2.72). 09/2009; 74(8):669-74. DOI: 10.1016/j.steroids.2009.02.007
Source: PubMed

ABSTRACT The androgen receptor (AR) is a ligand activated nuclear receptor, which regulates transcription and stimulates growth of androgen dependent prostate cancer. To regulate transcription, AR recruits a series of coactivators that modify chromatin and facilitate transcription. However, information on ligand and target gene-specific requirements for coactivators is limited. We compared the actions of the p160 coactivators SRC-1 and SRC-3/RAC3 with SRA (steroid receptor RNA activator). All three coactivate AR in the presence of agonist as expected. However, overexpression of either SRC-1 or SRC-3 increased AR activity in response to the partial antagonist, cyproterone acetate, whereas SRA was unable to stimulate AR activity under these conditions. Using siRNA to reduce expression of these coactivators in LNCaP cells, we also found promoter specific requirement for these coactivators. SRC-3 is required for optimal androgen dependent induction of PSA, TMPRSS2, and PMEPA1 whereas SRA is required only for optimal induction of the TMPRSS2 gene. These data indicate that different groups of AR target genes have distinct requirements for coactivators and response to AR ligands.

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    Androgen Receptors: Structural Biology, Genetics and Molecular Defects., 2014 edited by Silvia Socorro, 01/2014: chapter Structural and Functional Analysis of the Androgen Receptor in Disease: pages 53-81; Nova., ISBN: 978-1-62948-693-2
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    ABSTRACT: In normal prostate epithelium the TMPRSS2 gene encoding a type II serine protease is directly regulated by male hormones through the androgen receptor. In prostate cancer ERG protooncogene frequently gains hormonal control by seizing gene regulatory elements of TMPRSS2 through genomic fusion events. Although, the androgenic activation of TMPRSS2 gene has been established, little is known about other elements that may interact with TMPRSS2 promoter sequences to modulate ERG expression in TMPRSS2-ERG gene fusion context. Comparative genomic analyses of the TMPRSS2 promoter upstream sequences and pathway analyses were performed by the Genomatix Software. NKX3.1 and ERG genes expressions were evaluated by immunoblot or by quantitative Real-Time PCR (qRT-PCR) assays in response to siRNA knockdown or heterologous expression. QRT-PCR assay was used for monitoring the gene expression levels of NKX3.1-regulated genes. Transcriptional regulatory function of NKX3.1 was assessed by luciferase assay. Recruitment of NKX3.1 to its cognate elements was monitored by Chromatin Immunoprecipitation assay. Comparative analysis of the TMPRSS2 promoter upstream sequences among different species revealed the conservation of binding sites for the androgen inducible NKX3.1 tumor suppressor. Defects of NKX3.1, such as, allelic loss, haploinsufficiency, attenuated expression or decreased protein stability represent established pathways in prostate tumorigenesis. We found that NKX3.1 directly binds to TMPRSS2 upstream sequences and negatively regulates the expression of the ERG protooncogene through the TMPRSS2-ERG gene fusion. These observations imply that the frequently noted loss-of-function of NKX3.1 cooperates with the activation of TMPRSS2-ERG fusions in prostate tumorigenesis.
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