scholarly journals SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells

2009 ◽  
Vol 23 (3) ◽  
pp. 292-307 ◽  
Author(s):  
Sanna Kaikkonen ◽  
Tiina Jääskeläinen ◽  
Ulla Karvonen ◽  
Miia M. Rytinki ◽  
Harri Makkonen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Target Genes ◽  
Ectopic Expression ◽  
Prostate Cancer Cells ◽  
Intact Cells ◽  
Androgen Response Element ◽  
Isopeptidase Activity

Abstract The acceptor sites for small ubiquitin-like modifier (SUMO) are conserved in the N-terminal domains of several nuclear receptors. Here, we show that androgens induce rapid and dynamic conjugation of SUMO-1 to androgen receptor (AR). Nuclear import of AR is not sufficient for SUMOylation, because constitutively nuclear apo-ARs or antagonist-bound ARs are only very weakly modified by SUMO-1 in comparison with agonist-bound ARs. Of the SUMO-specific proteases (SENP)-1, -2, -3, -5, and -6, only SENP1 and SENP2 are efficient in cleaving AR-SUMO-1 conjugates in intact cells and in vitro. Both SENP1 and -2 are nuclear and found at sites proximal to AR. Their expression promotes AR-dependent transcription, but in a promoter-selective fashion. SENP1 and -2 stimulated the activity of holo-AR on compound androgen response element-containing promoters. The effects of SENP1 and -2 on AR-dependent transcription were dependent on catalytic activity and required intact SUMO acceptor sites in AR, indicating that their coactivating effects are mainly due to their direct isopeptidase activity on holo-AR. In prostate cancer cells, ectopic expression of SENP1, but not that of SENP2, increased the transcription activity of endogenous AR. Silencing of SENP1 attenuated the expression of several AR target genes and blunted androgen-stimulated growth of LNCaP cells. Our results indicate that SENP1 reverses the ligand-induced SUMOylation of AR and helps fine tune the cellular responses to androgens in a target promoter-selective manner.

scholarly journals TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth

2013 ◽  
Vol 21 (1) ◽  
pp. 127-142 ◽  
Author(s):  
Garrett Daniels ◽  
Yirong Li ◽  
Lan Lin Gellert ◽  
Albert Zhou ◽  
Jonathan Melamed ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Cancer Growth ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Dependent Growth

Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin β-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

scholarly journals 1α,25-Dihydroxyvitamin D3 Inhibits Growth of VCaP Prostate Cancer Cells Despite Inducing the Growth-Promoting TMPRSS2:ERG Gene Fusion

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1409-1417 ◽  
Author(s):  
Michele N. Washington ◽  
Nancy L. Weigel
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Target Gene ◽  
Target Genes ◽  
Fusion Gene ◽  
Critical Factor ◽  
Synthetic Analog ◽  
Prostate Cancer Cells ◽  
Dihydroxyvitamin D3

Vitamin D receptor (VDR) agonists have been shown to reduce the growth of several prostate cancer cell lines. However, the effects of VDR activation have not been examined in the presence of the recently identified androgen-regulated TMPRSS2:ERG gene fusions, which occur in a high percentage of prostate cancers and play a role in growth and invasiveness. In a previous microarray study, we found that VDR activation induces TMPRSS2 expression in LNCaP prostate cancer cells. Here we show that the natural VDR agonist 1α,25-dihydroxyvitamin D3 and its synthetic analog EB1089 increase expression of TMPRSS2:ERG mRNA in VCaP prostate cancer cells; this results in increased ETS-related gene (ERG) protein expression and ERG activity as demonstrated by an increase in the ERG target gene CACNA1D. In VCaP cells, we were not able to prevent EB1089-mediated TMPRSS2:ERG induction with an androgen receptor antagonist, Casodex, although in LNCaP cells, as reported for some other common androgen receptor and VDR target genes, Casodex reduces EB1089-mediated induction of TMPRSS2. However, despite inducing the fusion gene, VDR agonists reduce VCaP cell growth and expression of the ERG target gene c-Myc, a critical factor in VDR-mediated growth inhibition. Thus, the beneficial effects of VDR agonist treatment override some of the negative effects of ERG induction, although others remain to be tested.

scholarly journals Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells

2015 ◽  
Vol 26 (11) ◽  
pp. 1971-1984 ◽  
Author(s):  
Julia Lindqvist ◽  
Susumu Y. Imanishi ◽  
Elin Torvaldson ◽  
Marjo Malinen ◽  
Mika Remes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Target Genes ◽  
Growth Promotion ◽  
Intracellular Localization ◽  
Prostate Cancer Cells ◽  
Promoting Effect ◽  
Akt Activation

Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-depdent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.

scholarly journals Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

2019 ◽  
Author(s):  
Kalpit Shah ◽  
Teresa Gagliano ◽  
Lisa Garland ◽  
Timothy O’Hanlon ◽  
Daria Bortolotti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Therapeutic Interventions ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on anti-androgen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation- and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10099-10099
Author(s):  
R. Berger ◽  
D. I. Lin ◽  
M. Nieto ◽  
S. Signoretti ◽  
W. C. Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Prostate Cancer Cells ◽  
In Vivo Experiments ◽  
Her 2

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.

scholarly journals GADD45γ: a New Vitamin D-Regulated Gene that Is Antiproliferative in Prostate Cancer Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4654-4664 ◽  
Author(s):  
Omar Flores ◽  
Kerry L. Burnstein
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cell Cycle ◽  
Vitamin D ◽  
Androgen Receptor ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits proliferation of normal and malignant prostate epithelial cells at least in part through inhibition of G1 to S phase cell cycle progression. The mechanisms of the antiproliferative effects of 1,25-(OH)2D3 have yet to be fully elucidated but are known to require the vitamin D receptor. We previously developed a 1,25-(OH)2D3-resistant derivative of the human prostate cancer cell line, LNCaP, which retains active vitamin D receptors but is not growth inhibited by 1,25-(OH)2D3. Gene expression profiling revealed two novel 1,25-(OH)2D3-inducible genes, growth arrest and DNA damage-inducible gene gamma (GADD45γ) and mitogen induced gene 6 (MIG6), in LNCaP but not in 1,25-(OH)2D3-resistant cells. GADD45γ up-regulation was associated with growth inhibition by 1,25-(OH)2D3 in human prostate cancer cells. Ectopic expression of GADD45γ in either LNCaP or ALVA31 cells resulted in G1 accumulation and inhibition of proliferation equal to or greater than that caused by 1,25-(OH)2D3 treatment. In contrast, ectopic expression of MIG6 had only minimal effects on cell cycle distribution and proliferation. Whereas GADD45γ has been shown to be induced by androgens in prostate cancer cells, up-regulation of GADD45γ by 1,25-(OH)2D3 was not dependent on androgen receptor signaling, further refuting a requirement for androgens/androgen receptor in vitamin D-mediated growth inhibition. These data introduce two novel 1,25-(OH)2D3-regulated genes and establish GADD45γ as a growth-inhibitory protein in prostate cancer. Furthermore, the induction of GADD45γ gene expression by 1,25-(OH)2D3 may mark therapeutic response in prostate cancer.

scholarly journals The role of STEAP2 in aggressive prostate cancer traits and androgen response

2021 ◽  
Author(s):  
◽  
Leia A. Jones
Keyword(s):  
Prostate Cancer ◽  
Monoclonal Antibody ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Aggressive Prostate Cancer

The prognosis of localised prostate cancer is generally promising, as many tumours remain dormant and therefore do not require immediate intervention. In contrast, once metastasised, the prognosis for aggressive prostate cancer is often poor, highlighting the need for novel, effective treatment approaches. The expression of the six transmembrane epithelial antigen of the prostate2 (STEAP2) cell surface protein is increased in aggressive prostate cancer compared to normal prostate tissue. In vitro studies have shown STEAP2 to aid in prostate cancer progression, and as such this molecule shows promise as a potential novel therapeutic target in the treatment of advanced disease. The aim of this thesis was to develop a comprehensive understanding of the mechanistic role of STEAP2 in promoting aggressive prostate cancer traits and evaluate if its knock-out has the capacity to reduce the invasive potential of prostate cancer cells in vitro. As prostate cancer is a largely androgen dependent disease, this thesis also aimed to evaluate the effects of STEAP2 inhibition on the expression of the androgen receptor and androgen-regulated genes. This study developed and optimised a protocol for generating a set of 3D prostate cancer spheroids to provide more representative models of the in vivo prostate cancer environment. In this thesis, one commercial anti-STEAP2 polyclonal antibody and a panel of anti-STEAP2 monoclonal antibodies were selected for proof-of-concept studies where their effects on reducing prostate cancer cell viability were assessed. Receptor internalisation of STEAP2 was evaluated upon anti-STEAP2 monoclonal antibody binding to determine its suitability for use with antibody-drug conjugate technology. STEAP2 expression was knocked out using CRISPR/Cas9 genome engineering technology in two prostate cancer cell lines to evaluate its impact on cell proliferation, migration and invasion. Furthermore, gene expression profiling was conducted to explore interactions between STEAP2, the androgen receptor and a panel of androgen-regulated genes (PSA, FKBP5, GPRC6A and TMPRSS2) following: 1) anti-STEAP2 antibody treatment, 2) STEAP2-knockout and 3) the growth of prostate cancer cells in androgen-depleted conditions. The data presented in this thesis demonstrate that inhibition of STEAP2 by both the polyclonal anti-STEAP2 antibody and lead anti-STEAP2 monoclonal antibody significantly reduced prostate cancer cell viability. STEAP2 receptor internalisation was triggered following treatment of prostate cancer cells with the anti-STEAP2 monoclonal antibody, demonstrating its potential utility with antibody-drug conjugate technology in the future. STEAP2 knockout prostate cancer cells exhibited decreased cell proliferation, migration and invasion in comparison to wild-type cells. These promising findings highlight the therapeutic value of STEAP2-knockout in inhibiting invasive tumour cell traits. Gene expression data from both STEAP2-knockout cells and androgen-depleted cells suggest that STEAP2 may be involved in crosstalk between the androgen receptor and androgen-regulated genes. STEAP2 could therefore provide a novel target in conjunction with current conventional androgen deprivation therapy. In conclusion, the in vitro findings presented herein suggest STEAP2 as a viable target for the development of more tailored and personalised therapeutic agents to improve the clinical management of men with aggressive prostate cancer.

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