scholarly journals Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer

2013 ◽  
Vol 23 (11) ◽  
pp. 1797-1809 ◽  
Author(s):  
Sven Bilke ◽  
Raphaela Schwentner ◽  
Fan Yang ◽  
Maximilian Kauer ◽  
Gunhild Jug ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ewing Sarcoma ◽  
Target Genes

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

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 Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns

2012 ◽  
Vol 34 (2) ◽  
pp. 248-256 ◽  
Author(s):  
C. L. Doig ◽  
P. K. Singh ◽  
V. K. Dhiman ◽  
J. L. Thorne ◽  
S. Battaglia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Cancer Cells ◽  
Target Genes ◽  
Prostate Cancer Cells ◽  
Methylation Patterns

Anticancer Activity of Sweroside Nanoparticles in Prostate Cancer Bone Metastasis in PC-3 Cells Involved in Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 17 (10) ◽  
pp. 1960-1971
Author(s):  
Sheng Huang ◽  
Changye Zou ◽  
Shangyan Xie ◽  
Bin Wang ◽  
Xitao LingHu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Bone Metastasis ◽  
Cyclin D1 ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Target Genes ◽  
Downstream Target ◽  
Sphere Formation ◽  
In Cells

Bone metastasis is a significant cause of morbidity and mortality in patients with prostate cancer (PCa). This study is aimed at illustrating the mechanism of sweroside-mediated regulation in bone metastasis in PCa cells. Owing to the limitations of antitumor drugs in terms of their physical and chemical properties, making them into nanomaterials can effectively improve drug stability and bioavailability. Apoptosis was assessed with flow cytometry using the annexin V/propidium iodide binding assay; proteins, including p53, P21, Bcl-2, and Bax; and induction of intracellular reactive oxygen species (ROS). Using colony formation assay, sphere formation assay, and the expression changes in CD133 and CD44, stem cell characteristics were assessed. Epithelial–mesenchymal transition (EMT) activity was accessed by levels of the expression changes of EMT-related markers, vimentin and E-cadherin. Wnt/β-catenin signaling pathway was examined to detect the levels of the expression changes of snail and β-catenin. PC-3 cells were treated with lithium chloride (LiCl), which is an agonist of Wnt/β-catenin signaling, and the levels of CD133, CD44, vimentin, E-cadherin, snail, and β-catenin were detected. T-cell factor/lymphocyte enhancer factor (TCF/LEF) activity in cells overexpressing β-catenin was used to detect the effects on β-catenin transcription, and the expression of c-myc, Cyclin D1, Survivin, and MMP-7 were used to detect Wnt downstream target genes. Our results suggest that sweroside induces apoptosis and intracellular ROS; upregulates apoptotic proteins; and suppresses proliferation, invasion, and migration, preventing stem cell characteristics, including sphere formation, colony formation, and CD133 and CD44 expressions. Furthermore, sweroside nanoparticles exerts inhibitory effects on β-catenin transcription by suppressing TTCF/LEF activity in cells overexpressing β-catenin and downregulation of the expression of Wnt downstream target genes, including c-myc, Cyclin D1, Survivin, and MMP-7. The potential therapeutic effect of sweroside nanoparticles on bone metastatis of PCa was suggested, by these findings.

scholarly journals Differential Gene Expression in Patients With Prostate Cancer and in Patients With Parkinson Disease: an Example of Inverse Comorbidity

2021 ◽  
Author(s):  
Pietro Pepe ◽  
Simona Vetrano ◽  
Rossella Cannarella ◽  
Aldo E Calogero ◽  
Giovanna Marchese ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Causes Of Death ◽  
Genetic Factors ◽  
Target Genes ◽  
Lewy Bodies ◽  
Control Group ◽  
Healthy Donors ◽  
Differential Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies (LBs) and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named “inverse comorbidity”. The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. In the present study, next-generation sequencing (NGS) transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

scholarly journals Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jianneng Li ◽  
Mohammad Alyamani ◽  
Ao Zhang ◽  
Kai-Hsiung Chang ◽  
Michael Berk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Tumor Cells ◽  
Target Genes ◽  
Hydroxysteroid Dehydrogenase ◽  
Mouse Xenograft ◽  
Ubiquitin E3 Ligase ◽  
Metabolic Mechanism ◽  
Stimulation Of

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

scholarly journals Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

2020 ◽  
Vol 6 (18) ◽  
pp. eaaz8031 ◽  
Author(s):  
Leiming Wang ◽  
Chiang-Min Cheng ◽  
Jun Qin ◽  
Mafei Xu ◽  
Chung-Yang Kao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Receptor ◽  
High Throughput Screening ◽  
Target Gene ◽  
Target Genes ◽  
Orphan Nuclear Receptor ◽  
Prostate Cancer Treatment ◽  
Molecule Inhibitor ◽  
Transcription Regulators ◽  
Xenograft Models

The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII’s oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.

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.

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