scholarly journals Androgen Receptor-Related Non-coding RNAs in Prostate Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Yongyong Yang ◽  
Kilia Y. Liu ◽  
Qi Liu ◽  
Qi Cao
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Functional Roles ◽  
Castration Resistant ◽  
Number Of Patients ◽  
Non Coding Rnas

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. Androgen receptor (AR) signaling is the dominant oncogenic pathway in PCa and the main strategy of PCa treatment is to control the AR activity. A large number of patients acquire resistance to Androgen deprivation therapy (ADT) due to AR aberrant activation, resulting in castration-resistant prostate cancer (CRPC). Understanding the molecular mechanisms underlying AR signaling in the PCa is critical to identify new therapeutic targets for PCa patients. The recent advances in high-throughput RNA sequencing (RNA-seq) techniques identified an increasing number of non-coding RNAs (ncRNAs) that play critical roles through various mechanisms in different diseases. Some ncRNAs have shown great potentials as biomarkers and therapeutic targets. Many ncRNAs have been investigated to regulate PCa through direct association with AR. In this review, we aim to comprehensively summarize recent findings of the functional roles and molecular mechanisms of AR-related ncRNAs as AR regulators or targets in the progression of PCa.

scholarly journals Inhibition of enhancer of zeste homolog 2 (EZH2) overcomes enzalutamide resistance in castration-resistant prostate cancer

2019 ◽  
Vol 294 (25) ◽  
pp. 9911-9923 ◽  
Author(s):  
Yunfeng Bai ◽  
Zhuangzhuang Zhang ◽  
Lijun Cheng ◽  
Ruixin Wang ◽  
Xiaoliang Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Specific Antigen ◽  
The United States ◽  
Considerable Proportion ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Enhancer Of Zeste

Enzalutamide, approved by the United States Food and Drug Administration in 2018 for the management of metastatic castration-resistant prostate cancer (CRPC), is an androgen receptor (AR) inhibitor. It blocks androgen binding to the AR, AR nuclear translocation, and AR-mediated DNA binding. Unfortunately, a considerable proportion of tumors eventually develop resistance during the treatment. The molecular mechanisms underlying enzalutamide resistance are not completely understood. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressor complex 2, has been proposed as a prognostic marker for prostate cancer (PCa). With the goal to test whether EZH2 also plays a critical role in acquisition of enzalutamide resistance in CRPC, here we examined whether EZH2 inhibition/depletion enhances the efficacy of enzalutamide in enzalutamide-resistant PCa cells. We show that combining the EZH2 inhibitor GSK126 with enzalutamide synergistically inhibits cell proliferation and colony formation and promotes apoptosis in enzalutamide-resistant PCa cells. EZH2 depletion also overcomes enzalutamide resistance in both cultured cells and xenograft tumors. Mechanistically, we found that EZH2 directly binds to the promoter of prostate-specific antigen and inhibits its expression in enzalutamide-resistant PCa cells. In agreement, bioinformatics analysis of clinical RNA sequencing data involving GSEA indicated a strong correlation between AR and EZH2 gene expression during PCa progression. Our study provides critical insights into the mechanisms underlying enzalutamide resistance, which may offer new approaches to enhance the efficacy of enzalutamide in CRPC.

scholarly journals Androgen receptor variants: RNA-based mechanisms and therapeutic targets

2020 ◽  
Vol 29 (R1) ◽  
pp. R19-R26
Author(s):  
Kiel T Tietz ◽  
Scott M Dehm
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapies ◽  
Target Genes ◽  
Therapeutic Targets ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Growth And Survival ◽  
Androgen Receptor Variants ◽  
Active Transcription

Abstract Prostate cancer is the second leading cause of male cancer death in the United States. The androgen receptor (AR) transcription factor is a master regulator of normal glandular homeostasis in the prostate, as well as growth and survival of prostate cancer cells. Therefore, AR-targeted therapies are effective for improving overall survival of patients with advanced prostate cancer that is incurable by surgery or radiation. However, prostate cancer will inevitably progress on AR-targeted therapies to a castration-resistant prostate cancer (CRPC) phenotype that accounts for virtually all prostate cancer-specific death. mRNA transcript variants of the AR gene are expressed in CRPC cells and can be translated to produce AR variant (AR-V) proteins that function as ligand-independent, constitutively active transcription factors. AR-Vs are able to support growth of CRPC cells by promoting expression of AR target genes that are normally suppressed by AR-targeted therapies. Knowledge of mechanisms that govern expression of AR-Vs is incomplete. Studies have shown genomic rearrangements of the AR gene underlie expression of diverse AR-Vs in certain CRPC tumors, but post-transcriptional processes represent a broader regulatory mechanism for expression of AR-Vs in CRPC. This review focuses on alternative splicing, 3′ end processing, miRNA-mediated mRNA repression, of AR and AR-V expression and the potential these mechanisms hold as therapeutic targets for CRPC.

scholarly journals TR3 enhances AR Variant Production and Transactivation, Increasing Androgen Independency of AR Signaling in Prostate Cancer Cells

2021 ◽  
Author(s):  
Tuyen Thanh Tran ◽  
Keesook Lee
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Expression Level ◽  
Orphan Nuclear Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Androgen Independent

Abstract Background Increased expression of constitutively active androgen receptor variants (AR-Vs) is associated with the development of advanced castration-resistant prostate cancer. The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in various cancers including prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Methods Western blotting and quantitative RT-PCR were used to evaluate AR and AR-V expression levels affected by TR3 expression level. RNA-seq analysis, coimmunoprecipitation, cross-linked RNA-immunoprecipitation, and single-strand RNA protection and pull-down assays were conducted to elucidate the molecular mechanisms by which TR3 affected AR-V production. Results Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. Conclusions TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independency of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to advanced castration-resistant form.

Androgen receptor co-regulatory networks in castration-resistant prostate cancer

2013 ◽  
Vol 21 (1) ◽  
pp. R1-R11 ◽  
Author(s):  
Ying Ying Sung ◽  
Edwin Cheung
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Castration Resistant Prostate Cancer ◽  
Development Of Resistance ◽  
Castration Resistant ◽  
Transcriptional Regulatory ◽  
Preclinical And Clinical Studies

Androgen and the androgen receptor (AR) are critical effectors of prostate cancer. Consequently, androgen deprivation therapy is typically employed as a first-line treatment for prostate cancer patients. While initial responses are generally positive, prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer (CRPC). Recently, considerable effort has been directed toward elucidating the molecular mechanisms of CRPC. Results from both preclinical and clinical studies suggest that AR-mediated signaling persists and remains functionally important in CRPC despite the elimination of androgens. Understanding the role of this pathway in the development of resistance will therefore be critical to identify alternative diagnostic markers as well as more effective therapies for the treatment of CRPC. Using next-generation sequencing and other high-throughput approaches, numerous groups are beginning to identify the key differences in the transcriptional regulatory and gene expression programs between androgen-dependent and CRPC. A number of mechanisms have been proposed for the differences and these mostly involve alterations to components of the AR co-regulatory network. In this review, we summarize current knowledge on co-regulators of the AR and discuss their potential roles in CRPC. It is anticipated that a deeper understanding of these factors will undercover new targets that can assist in the diagnosis and treatment of CRPC.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

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