scholarly journals Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1

NAR Cancer ◽  
2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Taylor R Nicholas ◽  
Stephanie A Metcalf ◽  
Benjamin M Greulich ◽  
Peter C Hollenhorst
Keyword(s):  
Prostate Cancer ◽  
Ewing Sarcoma ◽  
Rnase H ◽  
Breakpoint Region ◽  
Polyadenylation Site ◽  
Multifunctional Protein ◽  
Promote Cell Migration ◽  
Early Transcription ◽  
Ewsr1 Gene ◽  
Dependent Mechanism

Abstract Ewing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5′ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5′ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5′ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to either early transcription termination, or breakpoint formation.

scholarly journals Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

2020 ◽  
Author(s):  
Taylor R. Nicholas ◽  
Peter C. Hollenhorst
Keyword(s):  
Prostate Cancer ◽  
Ewing Sarcoma ◽  
Rnase H ◽  
Breakpoint Region ◽  
Polyadenylation Site ◽  
Multifunctional Protein ◽  
Promote Cell Migration ◽  
Early Transcription ◽  
Oncogenic Gene ◽  
Dependent Mechanism

SummaryEwing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5’ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5’ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5’ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to early transcription termination and breakpoint formation.

A histone deacetylation-dependent mechanism for transcriptional repression of the gap junction gene cx43 in prostate cancer cells

The Prostate ◽  
2006 ◽  
Vol 66 (11) ◽  
pp. 1151-1161 ◽  
Author(s):  
Maite Hernandez ◽  
Qing Shao ◽  
Xiang-Jiao Yang ◽  
Shi-Ping Luh ◽  
Mustapha Kandouz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gap Junction ◽  
Cancer Cells ◽  
Transcriptional Repression ◽  
Histone Deacetylation ◽  
Prostate Cancer Cells ◽  
Dependent Mechanism

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

Is prostate-specific membrane antigen a multifunctional protein?

2005 ◽  
Vol 288 (5) ◽  
pp. C975-C981 ◽  
Author(s):  
Ayyappan K. Rajasekaran ◽  
Gopalakrishnapillai Anilkumar ◽  
Jason J. Christiansen
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Epithelial Cells ◽  
Therapeutic Target ◽  
Clinical Utility ◽  
Biological Function ◽  
Prostate Specific Membrane Antigen ◽  
Multifunctional Protein ◽  
Prostate Epithelial Cells ◽  
Specific Membrane

Prostate-specific membrane antigen (PSMA) is a metallopeptidase expressed predominantly in prostate cancer (PCa) cells. PSMA is considered a biomarker for PCa and is under intense investigation for use as an imaging and therapeutic target. Although the clinical utility of PSMA in the detection and treatment of PCa is evident and is being pursued, very little is known about its basic biological function in PCa cells. The purpose of this review is to highlight the possibility that PSMA might be a multifunctional protein. We suggest that PSMA may function as a receptor internalizing a putative ligand, an enzyme playing a role in nutrient uptake, and a peptidase involved in signal transduction in prostate epithelial cells. Insights into the possible functions of PSMA should improve the diagnostic and therapeutic values of this clinically important molecule.

scholarly journals PLCɛ maintains the functionality of AR signaling in prostate cancer via an autophagy-dependent mechanism

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Zhen Quan ◽  
Ting Li ◽  
Yang Xia ◽  
Jiayu Liu ◽  
Zhongbo Du ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Cell Migration ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Cell Models ◽  
Autophagic Activity ◽  
Underlying Mechanisms ◽  
Signaling Activity ◽  
Dependent Mechanism

Abstract Androgen receptor (AR) signaling is a major driver of prostate cancer (CaP). Although most therapies targeting AR are initially effective in CaP patients, drug resistance is inevitable, mainly because of the inappropriate re-activation of AR pathway. However, the underlying mechanisms remain largely unknown. Here, we found that phospholipase C epsilon (PLCɛ) was highly expressed in CaP samples, and was closely associated with AR signaling activities. PLCɛ depletion triggered enhanced autophagic activities via AMPK/ULK1 pathway, causing autophagy-mediated AR degradation and inhibition of AR nuclear translocation. This subsequently reduced AR signals in CaP and inhibited AR-driven cell migration/invasion. Furthermore, a positive correlation between PLCɛ and AR signaling activity was also observed in bicalutamide-resistant CaP samples and in AR-antagonist-resistant CaP cell models. PLCɛ depletion resulted in the failure to establish AR-antagonist-resistant CaP cell lines, and hindered the metastatic prowess of already established ones. These findings suggest that PLCɛ-mediated autophagic activity alteration is indispensible for the functionality of AR signaling and for CaP development.

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