scholarly journals ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Zineb Mounir ◽  
Joshua M Korn ◽  
Thomas Westerling ◽  
Fallon Lin ◽  
Christina A Kirby ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Methylation Site ◽  
Prostate Cancer Cells ◽  
Arginine Methyltransferase ◽  
Inhibitory Function ◽  
Lineage Differentiation ◽  
Prostate Cancers ◽  
Prostate Epithelium

The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR’s ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.

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 Cold Atmospheric Plasma Selectively Induces G0/G1 Cell Cycle Arrest and Apoptosis in AR-Independent Prostate Cancer Cells

2020 ◽  
Author(s):  
Meng Ning ◽  
Zhifa Zhang ◽  
Lihui Yu ◽  
Peiyu Han ◽  
xiaofeng Dai
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Atmospheric Plasma ◽  
Prostate Cancer Cells ◽  
Cold Atmospheric Plasma ◽  
Prostate Cancers ◽  
And Migration ◽  
Physical Plasma

Abstract BackgroundAndrogen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies.Methods We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells.ResultsWe show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. ConclusionOur study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

scholarly journals Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2944
Author(s):  
Zoran Culig
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cellular Response ◽  
Target Genes ◽  
Neuroendocrine Differentiation ◽  
Cancer Tissue ◽  
Androgen Ablation ◽  
Prostate Cancers

Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.

scholarly journals Activation of the Androgen Receptor gene by BORIS/CTCFL in prostate cancer cells

2017 ◽  
Author(s):  
Yukti Hari-Gupta ◽  
Georgia-Xanthi Kita ◽  
Dawn Farrar ◽  
Elena Klenova
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Critical Role ◽  
Prostate Gland ◽  
Biologically Active ◽  
Ctcf Binding ◽  
Prostate Cancer Cells ◽  
Prostate Cancers

AbstractBORIS/CTCFL, a paralogue of the chromatin architectural protein CTCF, is a member of the cancer-testis antigen family, normally present in the testes. BORIS is expressed in various tumours, including prostate cancers, however the function of BORIS in cancer cells is not well defined. The androgen receptor (AR) plays a critical role in the normal development of a human prostate gland and pathogenesis of prostate cancer. In our previous study we described a positive correlation between elevated levels of BORIS and AR in prostate cancers, and activation of the AR gene by BORIS in prostate cancer cells. Elucidation of the mechanisms involved in the modulation of AR activity is important to understand prostate tumourigenesis and investigation of transcriptional regulation of the AR gene by BORIS may provide new insights into this issue. Here we report the ability of BORIS to not only positively regulate AR in androgen-dependent prostate cancer (ADPC) cells, but re-activate epigenetically silenced AR in androgen-independent prostate cancer (AIPC) cells leading to the production of biologically active AR protein. CTCF, on the other hand, had repressive effects on the AR. In both, ADPC and AIPC cells, introduction of ectopic BORIS was associated with the reduction in the AR promoter methylation, increase in active and decrease in repressive chromatin marks, and decrease in CTCF occupancies at the two main upstream BORIS/CTCF binding sites. We propose a model of epigenetic regulation of AR by BORIS in prostate cells whereby BORIS remodels the chromatin at the AR promoter leading to transcriptional activation.

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.

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.

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