GLI3 is stabilized by SPOP mutations and promotes castration resistance via functional cooperation with androgen receptor in prostate cancer

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.

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Long noncoding RNA CRAT1 inhibits castration-resistance of prostate cancer via inhibiting androgen receptor protein translation

European Urology Supplements ◽

10.1016/s1569-9056(19)30049-1 ◽

2019 ◽

Vol 18 (1) ◽

pp. e65

Author(s):

C. Xu ◽

G. Peng ◽

X. Ruihui ◽

H. Ming ◽

Z. Qianghua ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Protein Translation ◽

Receptor Protein ◽

Castration Resistance ◽

Androgen Receptor Protein

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Slug, a Unique Androgen-Regulated Transcription Factor, Coordinates Androgen Receptor to Facilitate Castration Resistance in Prostate Cancer

Molecular Endocrinology ◽

10.1210/me.2011-1360 ◽

2012 ◽

Vol 26 (9) ◽

pp. 1496-1507 ◽

Cited By ~ 34

Author(s):

Kaijie Wu ◽

Crystal Gore ◽

Lin Yang ◽

Ladan Fazli ◽

Martin Gleave ◽

...

Keyword(s):

Prostate Cancer ◽

Transcription Factor ◽

Androgen Receptor ◽

Castration Resistance

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Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Journal of Clinical Investigation ◽

10.1172/jci41824 ◽

2010 ◽

Vol 120 (8) ◽

pp. 2715-2730 ◽

Cited By ~ 466

Author(s):

Shihua Sun ◽

Cynthia C.T. Sprenger ◽

Robert L. Vessella ◽

Kathleen Haugk ◽

Kathryn Soriano ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variant ◽

Human Prostate ◽

Human Prostate Cancer ◽

Castration Resistance ◽

Androgen Receptor Splice Variant

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Extragonadal Steroids Contribute Significantly to Androgen Receptor Activity and Development of Castration Resistance in Recurrent Prostate Cancer after Primary Therapy

The Journal of Urology ◽

10.1097/ju.0000000000000699 ◽

2020 ◽

Vol 203 (5) ◽

pp. 940-948

Author(s):

Frédéric Pouliot ◽

Mélanie Rouleau ◽

Bertrand Neveu ◽

Paul Toren ◽

Fannie Morin ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Receptor Activity ◽

Primary Therapy ◽

Castration Resistance ◽

Recurrent Prostate Cancer ◽

Androgen Receptor Activity

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Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation

Nucleic Acids Research ◽

10.1093/nar/gkz1004 ◽

2019 ◽

Author(s):

Lingling Duan ◽

Zhenhua Chen ◽

Jun Lu ◽

Yanping Liang ◽

Ming Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Alternative Splicing ◽

Chromatin Accessibility ◽

Splicing Factor ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Cryptic Exon ◽

Genome Wide ◽

Lysine Demethylase

Abstract Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5′-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.

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MicroRNA Regulation of Androgen Receptor in Castration-Resistant Prostate Cancer: Premises, Promises, and Potentials

Current Molecular Pharmacology ◽

10.2174/1874467213666201223121850 ◽

2020 ◽

Vol 13 ◽

Author(s):

Safieh Ebrahimi ◽

Seyed Isaac Hashemy ◽

Amirhossein Sahebkar ◽

Seyed Hamid AghaeeBakhtiari

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Therapeutic Potential ◽

Splice Variants ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Contributing Factors ◽

Development Of Resistance ◽

Castration Resistant

: Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration-resistant prostate cancer (CRPC), continues to be a major obstacle against successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, ARrelated signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies including miRNAs and existing drugs can synergistically decrease castration resistance. miRNAs have also prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.

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