scholarly journals Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

2004 ◽  
Vol 379 (3) ◽  
pp. 731-738 ◽  
Author(s):  
Cor A. BERREVOETS ◽  
Arzu UMAR ◽  
Jan TRAPMAN ◽  
Albert O. BRINKMANN
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Conformational Change ◽  
Nuclear Receptor ◽  
Cyproterone Acetate ◽  
Transcriptional Activity ◽  
Differential Modulation ◽  
Partial Agonists ◽  
Receptor Action

Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877→Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

scholarly journals Differential modulation of the androgen receptor for prostate cancer therapy depends on the DNA response element

2020 ◽  
Vol 48 (9) ◽  
pp. 4741-4755
Author(s):  
Steven Kregel ◽  
Pia Bagamasbad ◽  
Shihan He ◽  
Elizabeth LaPensee ◽  
Yemi Raji ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Target Genes ◽  
Normal Growth ◽  
Differential Modulation ◽  
Expression Of Genes ◽  
Prostate Cancer Therapy ◽  
Specific Factors

Abstract Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.

Chrebp regulates the transcriptional activity of androgen receptor in prostate cancer

Tumor Biology ◽  
2014 ◽  
Vol 35 (8) ◽  
pp. 8143-8148 ◽  
Author(s):  
Xue-Lei Wang ◽  
Xiao-Fei Wen ◽  
Rong-Bing Li ◽  
Bin Liu ◽  
Guang-Ming Qiu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Transcriptional Activity

scholarly journals BAP18 coactivates androgen receptor action and promotes prostate cancer progression

2016 ◽  
Vol 44 (17) ◽  
pp. 8112-8128 ◽  
Author(s):  
Shiying Sun ◽  
Xinping Zhong ◽  
Chunyu Wang ◽  
Hongmiao Sun ◽  
Shengli Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Receptor Action

scholarly journals c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

EBioMedicine ◽  
2017 ◽  
Vol 18 ◽  
pp. 83-93 ◽  
Author(s):  
Stefan J. Barfeld ◽  
Alfonso Urbanucci ◽  
Harri M. Itkonen ◽  
Ladan Fazli ◽  
Jessica L. Hicks ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Gene Networks ◽  
Transcriptional Activity

scholarly journals Differential Modulation of Androgen Receptor Action by Deoxyribonucleic Acid Response Elements

2003 ◽  
Vol 17 (9) ◽  
pp. 1738-1750 ◽  
Author(s):  
Christoph Geserick ◽  
Hellmuth-Alexander Meyer ◽  
Karina Barbulescu ◽  
Bernard Haendler
Keyword(s):  
Androgen Receptor ◽  
Deoxyribonucleic Acid ◽  
Differential Modulation ◽  
Response Elements ◽  
Receptor Action

scholarly journals A Splicing Variant of the Androgen Receptor Detected in a Metastatic Prostate Cancer Exhibits Exclusively Cytoplasmic Actions

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4334-4343 ◽  
Author(s):  
Monika Jagla ◽  
Marie Fève ◽  
Pascal Kessler ◽  
Gaëlle Lapouge ◽  
Eva Erdmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Dna Binding ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Splicing Variant ◽  
Activation Of Transcription

The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-κB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.

scholarly journals Potentiation of androgen receptor transcriptional activity by inhibition of histone deacetylation--rescue of transcriptionally compromised mutants

2004 ◽  
Vol 182 (3) ◽  
pp. 377-389 ◽  
Author(s):  
CG Korkmaz ◽  
K Fronsdal ◽  
Y Zhang ◽  
PI Lorenzo ◽  
F Saatcioglu
Keyword(s):  
Androgen Receptor ◽  
Histone Acetylation ◽  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Trichostatin A ◽  
Specific Antigen ◽  
Histone Deacetylation ◽  
Lncap Cells ◽  
Viral Oncoprotein

Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated by the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. We and others have previously shown that CREB-binding protein (CBP) can function as a coactivator for AR. Similar to some other nuclear receptor coactivators and/or the proteins that they interact with, CBP has histone acetyl transferase (HAT) activity that is thought to contribute to transcriptional activation by nuclear receptors. We have therefore assessed whether an increase in the histone acetylation status in the cell can influence AR transcriptional activity, by using the histone deacetylase (HDAC) inhibitors (HDACIs) trichostatin A (TSA), sodium butyrate (Na-But) and depsipeptide (FR901228). We found that inhibition of HDAC activity significantly increased the ability of endogenous AR in LNCaP cells, or ectopically expressed AR in HeLa cells, to activate transcription from AR-dependent reporter constructs. In addition, HDACIs increased the androgen-dependent activation of the prostate-specific antigen (PSA) gene in LNCaP cells, an increase that was not due to an increase in nuclear AR protein levels. Moreover, the viral oncoprotein E1A that inhibits CBP HAT activity fully repressed the ability of HDACIs to stimulate AR-mediated transcription, indicating that CBP is involved in this process. Deletional mutagenesis of AR indicated that whereas the AF-2 domain in the C-terminus is dispensable, the AF-1 domain in the N-terminus is required for augmentation of AR action by HDACIs, an observation which is in concordance with the reduced ability of CBP to activate AR N-terminal deletion mutants. Furthermore, HDACI treatment rescued the deficiency in the transactivation potential of AF-2 mutants. Taken together, our findings suggest that a change in the level of histone acetylation of target genes is an important determinant of AR action, possibly mediated by CBP.

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