scholarly journals Locus-Wide Chromatin Remodeling and Enhanced Androgen Receptor-Mediated Transcription in Recurrent Prostate Tumor Cells

2006 ◽  
Vol 26 (19) ◽  
pp. 7331-7341 ◽  
Author(s):  
Li Jia ◽  
Howard C. Shen ◽  
Marcus Wantroba ◽  
Omar Khalid ◽  
Gangning Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Specific Antigen ◽  
Entire Body ◽  
Prostate Cancers ◽  
Prostate Tumor Cells ◽  
Androgen Independent

ABSTRACT Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.

Hormonal therapy of prostate cancer

2011 ◽  
pp. 1622-1634
Author(s):  
Ciara O’Hanlon Brown ◽  
Jonathan Waxman
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Specific Antigen ◽  
Intraepithelial Neoplasia ◽  
Peripheral Zone ◽  
Molecular Feature ◽  
Molecular Defects ◽  
Psa Testing ◽  
Seer Data ◽  
Prostate Cancers

Prostate cancer is the most common cancer to effect men and the second most common cause of cancer-related death. Premalignant change or prostatic intraepithelial neoplasia has been detected within the prostate glands of men under 30 years of age. The incidence of prostate cancer remains negligible until men reach their 40s from whence it rises steadily and by 80 years 70% of men have detectable tumours at autopsy (1). A majority of prostate cancers arise from the peripheral zone of the prostate and rarely cause obstructive symptoms. Consequently, prostate cancers have historically presented late, with symptoms of metastatic disease. The advent of prostate-specific antigen (PSA) testing has produced a stage shift so that at present over 90% of prostate cancers are diagnosed as organ-confined disease. PSA diagnosis has unmasked a subset of prostate tumours that exhibit an indolent growth pattern and appear destined to remain organ-confined tumours the patient dies with, and not from. US SEER data estimates a 50-year-old man has a 42% chance of developing prostate cancer but only a 3.6% chance of dying from the disease. Features, either clinical or molecular, which would allow clinicians to clearly differentiate indolent from aggressive disease while still at the organ-confined stage, have yet to be identified (1). Adenocarcinoma is the predominant histological subtype of prostate cancer, accounting for 95% of tumours. Prostatic adenocarcinomas arise from androgen receptor-positive epithelial cells. On histological examination, prostate cancers appear multifocal and demonstrate heterogeneity both within individual tumours and across populations. This has created an obstacle as researchers attempt to subclassify prostate cancer and identify the molecular defects responsible for driving prostatic carcinogenesis (1). Of prostate cancers, 80–90% are androgen receptor-positive at diagnosis (2), thus to date the androgen–androgen receptor axis is the sole molecular feature of this disease that has been successfully harnessed as a therapeutic target.

scholarly journals The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus

2005 ◽  
Vol 34 (1) ◽  
pp. 107-118 ◽  
Author(s):  
J Kim ◽  
L Jia ◽  
M R Stallcup ◽  
G A Coetzee
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Androgen Receptor ◽  
Protein Kinase ◽  
Specific Antigen ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Camp Responsive Element Binding ◽  
Kinase A ◽  
Androgen Independent

Androgen-independent prostate cancer is a lethal form of the disease that is marked by metastasis and rapid proliferation in its final stages. As no effective therapy for this aggressive tumor currently exists, it is imperative to elucidate and target the mechanisms involved in the progression to androgen independence. Accumulating evidence indicates that aberrant activation of androgen receptor (AR) via signal transduction pathways, AR gene mutation and/or amplification, and/or coregulator alterations may contribute to the progression of prostate cancer. In the present study, the effects of protein kinase A (PKA) signaling and its downstream factors on AR activity at the prostate-specific antigen (PSA) gene were tested. Activation of PKA by forskolin resulted in enhanced androgen-induced expression of the PSA gene, an effect that was blocked by the AR antagonist, bicalutamide. Interestingly, when either p300 or CBP was overexpressed, PKA activation was sufficient to stimulate PSA promoter-driven transcription in the absence of androgen, which was not inhibited by bicalutamide. PKA activation did not significantly alter AR protein levels but significantly increased the phosphorylated form of its downstream effector, cAMP responsive element-binding protein (CREB) in the presence of androgen. Furthermore, chromatin immunoprecipitation showed that the combination of androgen and forskolin increased phosphorylated CREB occupancy, which was accompanied by histone acetylation, at the putative cAMP responsive element located in the 5′ upstream regulatory region of the PSA gene. Remarkably, mammalian two-hybrid assay indicated that p300/CBP may bridge the interaction between AR and CREB, suggesting a novel enhanceosomal cooperation. These results demonstrate an intriguing interplay between a signal transduction pathway, coactivator overexpression and AR signaling as a possible combined mechanism of progression to androgen-independent prostate cancer.

IMMUNOLOCALIZATION OF APOLIPOPROTEIN D, ANDROGEN RECEPTOR AND PROSTATE SPECIFIC ANTIGEN IN EARLY STAGE PROSTATE CANCERS

1998 ◽  
Vol 159 (2) ◽  
pp. 548-554 ◽  
Author(s):  
Steven X.D. Zhang ◽  
Jacqueline M. Bentel ◽  
Carmela Ricciardelli ◽  
David J. Horsfall ◽  
Darrow E. Haagensen ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Prostate Specific Antigen ◽  
Early Stage ◽  
Specific Antigen ◽  
Apolipoprotein D ◽  
Prostate Cancers

scholarly journals CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes

2008 ◽  
Vol 28 (12) ◽  
pp. 3894-3904 ◽  
Author(s):  
Brandi A. Thompson ◽  
Véronique Tremblay ◽  
Grace Lin ◽  
Daniel A. Bochar
Keyword(s):  
Gene Expression ◽  
Rna Interference ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Chromatin Structure ◽  
Target Genes ◽  
Promoter Regions ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Targeted Gene Expression

ABSTRACT ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription. Here we report that full-length CHD8 interacts directly with β-catenin and that CHD8 is also recruited specifically to the promoter regions of several β-catenin-responsive genes. Our results indicate that CHD8 negatively regulates β-catenin-targeted gene expression, since short hairpin RNA against CHD8 results in the activation of several β-catenin target genes. This regulation is also conserved through evolution; RNA interference against kismet, the apparent Drosophila ortholog of CHD8, results in a similar activation of β-catenin target genes. We also report the first demonstration of chromatin remodeling activity for a member of the CHD6-9 family of proteins, suggesting that CHD8 functions in transcription through the ATP-dependent modulation of chromatin structure.

scholarly journals Hey1, a Mediator of Notch Signaling, Is an Androgen Receptor Corepressor

2005 ◽  
Vol 25 (4) ◽  
pp. 1425-1436 ◽  
Author(s):  
Borja Belandia ◽  
Sue M. Powell ◽  
Juana M. García-Pedrero ◽  
Marjorie M. Walker ◽  
Charlotte L. Bevan ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Notch Signaling ◽  
Target Genes ◽  
Active Form ◽  
Prostatic Hyperplasia ◽  
Transcriptional Repressors ◽  
Marked Contrast ◽  
Hormonal Responses ◽  
Helix Loop Helix ◽  
Prostate Cancers

ABSTRACT Hey1 is a member of the basic helix-loop-helix-Orange family of transcriptional repressors that mediate Notch signaling. Here we show that transcription from androgen-dependent target genes is inhibited by Hey1 and that expression of a constitutively active form of Notch is capable of repressing transactivation by the endogenous androgen receptor (AR). Our results indicate that Hey1 functions as a corepressor for AF1 in the AR, providing a mechanism for cross talk between Notch and androgen-signaling pathways. Hey1 colocalizes with AR in the epithelia of patients with benign prostatic hyperplasia, where it is found in both the cytoplasm and the nucleus. In marked contrast, we demonstrate that Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer.

scholarly journals TAF1 Differentially Enhances Androgen Receptor Transcriptional Activity via Its N-Terminal Kinase and Ubiquitin-Activating and -Conjugating Domains

2010 ◽  
Vol 24 (4) ◽  
pp. 696-708 ◽  
Author(s):  
Peyman Tavassoli ◽  
Latif A. Wafa ◽  
Helen Cheng ◽  
Amina Zoubeidi ◽  
Ladan Fazli ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Specific Antigen ◽  
Tissue Microarrays ◽  
Compensatory Mechanism ◽  
Castration Resistance ◽  
Aberrant Expression ◽  
Androgen Withdrawal ◽  
Prostate Cancers

Abstract Aberrant expression of androgen receptor (AR) coregulators has been linked to progression of prostate cancers to castration resistance. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. Glutathione S-transferase pulldown assays established that TAF1 bound through its acetylation and ubiquitin-activating/conjugating domains (E1/E2) directly to the AR N terminus. Coimmunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate-specific antigen promoter/enhancer in prostate cancer cells. With respect to modulation of AR activity, overexpression of TAF1 enhanced AR activity severalfold, whereas small interfering RNA knockdown of TAF1 significantly decreased AR transactivation. Although full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity by TAF1 was demonstrated in transactivation experiments using cloned N-terminal kinase and E1/E2 functional domains. In keeping with AR coactivation by the ubiquitin-activating and -conjugating domain, TAF1 was found to greatly increase the cellular amount of polyubiquitinated AR. In conclusion, our results indicate that increased TAF1 expression is associated with progression of human prostate cancers to the lethal castration-resistant state. Because TAF1 is a coactivator of AR that binds and enhances AR transcriptional activity, its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens.

scholarly journals BRG1-Mediated Chromatin Remodeling Regulates Differentiation and Gene Expression of T Helper Cells

2008 ◽  
Vol 28 (24) ◽  
pp. 7274-7285 ◽  
Author(s):  
Andrea L. Wurster ◽  
Michael J. Pazin
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Target Genes ◽  
T Helper Cell ◽  
T Helper ◽  
T Helper 2 ◽  
Th2 Cytokine ◽  
Th2 Differentiation

ABSTRACT During T helper cell differentiation, distinct programs of gene expression play a key role in defining the immune response to an environmental challenge. How chromatin remodeling events at the associated cytokine loci control differentiation is not known. We found that the ATP-dependent remodeling enzyme subunit BRG1 was required for T helper 2 (Th2) differentiation and Th2 cytokine transcription. BRG1 binding to cytokine genes was regulated by the extent of differentiation, the extent of activation, and cell fate. BRG1 was required for some features of the chromatin structure in target genes (DNase I hypersensitivity and histone acetylation), suggesting that BRG1 remodeling activity was directly responsible for changes in gene expression. NFAT and STAT6 activity were required for BRG1 recruitment to the Th2 locus control region, and STAT6 associated with BRG1 in a differentiation-inducible manner, suggesting direct recruitment of BRG1 to the bound loci. Together, these findings suggest BRG1 interprets differentiation signals and plays a causal role in gene regulation, chromatin structure, and cell fate.

scholarly journals Epigenetic Regulation of Androgen Receptor Gene Expression in Human Prostate Cancers

2000 ◽  
Vol 80 (12) ◽  
pp. 1789-1796 ◽  
Author(s):  
Tsuyoshi Nakayama ◽  
Masatoshi Watanabe ◽  
Hiroyoshi Suzuki ◽  
Minoru Toyota ◽  
Nobuyuki Sekita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Epigenetic Regulation ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Human Prostate ◽  
Prostate Cancers ◽  
Receptor Gene Expression

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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