Oncogenicity and Selective Inhibition of ERG Splicing Variants in Prostate Cancer

2012 ◽  
Author(s):  
Luca Cartegni ◽  
George Boutsalis ◽  
Gina Rocco ◽  
Francesca Zammarchi
Keyword(s):  
Prostate Cancer ◽  
Selective Inhibition ◽  
Splicing Variants

scholarly journals Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yuan Liu ◽  
Cuifu Yu ◽  
Zhenlong Shao ◽  
Xiaohong Xia ◽  
Tumei Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Selective Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Selective Degradation ◽  
Castration Resistant ◽  
Novel Drugs ◽  
The Stability ◽  
Androgen Receptor Splice Variant

AbstractAndrogen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

scholarly journals KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor

2014 ◽  
Vol 57 (14) ◽  
pp. 5975-5985 ◽  
Author(s):  
Chia-Han Chu ◽  
Ling-Yu Wang ◽  
Kai-Cheng Hsu ◽  
Chung-Chin Chen ◽  
Hsing-Hung Cheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Structural Analysis ◽  
Selective Inhibition

scholarly journals Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer

2020 ◽  
Vol 9 (6) ◽  
pp. 1703
Author(s):  
Prudencio Sáez-Martínez ◽  
Juan M. Jiménez-Vacas ◽  
Antonio J. León-González ◽  
Vicente Herrero-Aguayo ◽  
Antonio J. Montero Hidalgo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Potential ◽  
Molecular Response ◽  
Oncogenic Signaling ◽  
Antitumor Effects ◽  
Normal Prostate ◽  
Migration Rates ◽  
Splicing Variants ◽  
Pathophysiological Role ◽  
Oncogenic Signaling Pathways

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer

Nature ◽  
2020 ◽  
Vol 578 (7794) ◽  
pp. 306-310 ◽  
Author(s):  
Emily J. Faivre ◽  
Keith F. McDaniel ◽  
Daniel H. Albert ◽  
Srinivasa R. Mantena ◽  
Joshua P. Plotnik ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Selective Inhibition
Sign in / Sign up

Export Citation Format

Share Document