scholarly journals DNA binding alters ARv7 dimer interactions

2021 ◽  
Author(s):  
F. Özgün ◽  
Z. Kaya ◽  
T. Morova ◽  
B. Geverts ◽  
T.E. Abraham ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Conformational Changes ◽  
Splice Variants ◽  
Receptor Interaction ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Close Proximity ◽  
Androgen Receptor Splice Variant ◽  
The Individual

Androgen receptor (AR) splice variants are described as one of the potential drivers of lethal castration-resistant prostate cancer. Androgen receptor splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation antiandrogens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining FRET and FRAP we demonstrate that these heterodimers undergo conformational changes following DNA binding indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible, high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homo- or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.

scholarly journals Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3488
Author(s):  
Fuqiang Ban ◽  
Eric Leblanc ◽  
Ayse Derya Cavga ◽  
Chia-Chi Flora Huang ◽  
Mark R. Flory ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variants ◽  
Full Length ◽  
Cancer Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Terminal Domain ◽  
Castration Resistant ◽  
Coregulatory Proteins ◽  
Androgen Binding

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.

scholarly journals Data of relative mRNA and protein abundances of androgen receptor splice variants in castration-resistant prostate cancer

Data in Brief ◽  
2021 ◽  
Vol 34 ◽  
pp. 106774
Author(s):  
Tianfang Ma ◽  
Nathan Ungerleider ◽  
Derek Y. Zhang ◽  
Eva Corey ◽  
Erik K. Flemington ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Androgen Receptor Splice 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.

Expression pattern of androgen receptors, AR-V7 and AR-567es, in circulating tumor cells and paired plasma-derived extracellular vesicles in metastatic castration resistant prostate cancer

The Analyst ◽  
2019 ◽  
Vol 144 (22) ◽  
pp. 6671-6680 ◽  
Author(s):  
Areti Strati ◽  
Martha Zavridou ◽  
Evangelos Bournakis ◽  
Sophia Mastoraki ◽  
Evi Lianidou
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Androgen Receptors ◽  
Acquired Resistance ◽  
Predictive Biomarker ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Inhibitors ◽  
Androgen Receptor Splice Variant

Androgen-receptor splice variant 7 (AR-V7) is a highly promising liquid biopsy predictive biomarker showing primary or acquired resistance to novel androgen receptor signaling inhibitors in metastatic castration resistant prostate cancer (mCRPC).

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