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Androgen Receptor and AR-Related Signaling in Health and Disease

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A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (20 July 2022) | Viewed by 22089

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Dr. Thomas Greither

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Guest Editor

Center for Reproductive Medicine and Andrology, University Hospital, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany
Interests: androgens; spermatogenesis; infertility; adipogenesis; prostate carcinoma; soft tissue sarcoma; OSCC

Dr. Sven Wach

E-Mail Website
Guest Editor

Department of Urology and Pediatric Urology, University Hospital, FAU Erlangen-Nürnberg, Maximilianspl. 2, 91054 Erlangen, Germany
Interests: androgen receptor; AR variants; prostate carcinoma

Special Issue Information

Dear Colleagues,

The androgen receptor (AR) is an important member of the class I nuclear receptor transcription factor family. AR signaling is mainly induced by AR binding to its natural ligand testosterone or its bioactive form dihydrotestosterone (DHT), followed by translocation to the nucleus and binding of the complex to androgen-responsive elements (AREs) in the promoter region of its target genes. Dependent on the co-factors recruited to the AR–ARE complex, transcription of the target gene may be either induced through co-activators or repressed through co-repressors. Over 1500 target genes are estimated to be transcriptionally regulated by the AR signaling pathway, including protein-coding genes like prostate-specific antigen (PSA), TMPRSS2, and SERPINB5, as well as non-coding RNAs like miR-125b, miR-21, or the long non-coding (lnc)RNA MALAT1.

Besides others, AR signaling plays a crucial role in physiological processes like muscle growth, maintenance of the prostate tissue, spermatogenesis, and development of the male phenotype, as well as in female reproductive processes like ovarian folliculogenesis. On the other hand, dysregulated AR signaling is strongly correlated to tumorigenesis and progression of hormone-sensitive tumors like prostate carcinoma and breast cancer and may also play a pivotal role in other tumor entities.

Taken together, although there are well-established connections between the mechanisms of AR signaling, some target genes regulated by the AR, and physiological or pathophysiological processes influenced by these pathways, many elements in the complex interplay between the AR-regulated transcriptome, signaling pathways altered by AR dysregulation, and the resulting changes in cellular phenotype as well as putative pathophysiological consequences remain to be elucidated.

Dr. Thomas Greither
Dr. Sven Wach
Guest Editors

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Keywords

Androgen receptor
AR signaling
Prostate carcinoma
Breast cancer
hypogonadism

Published Papers (9 papers)

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Research

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15 pages, 3868 KiB

Open AccessArticle

AC016745.3 Regulates the Transcription of AR Target Genes by Antagonizing NONO

by Yali Lu, Xuechao Wan, Wenhua Huang, Lu Zhang, Jun Luo, Dujian Li, Yan Huang, Yao Li and Yaoting Xu

Life 2021, 11(11), 1208; https://doi.org/10.3390/life11111208 - 09 Nov 2021

Cited by 2 | Viewed by 1422

Abstract

The androgen receptor (AR) and its related signaling pathways play an important role in the development of prostate cancer (PCa). Long non-coding RNAs (lncRNAs) are involved in the regulation of tumorigenesis and development, but their specific mechanism of action remains unclear. This study examines the function and mechanisms of action of lncRNA AC016745.3 in the development of PCa. It shows that dihydrotestosterone (DHT) results in the AR-dependent suppression of AC016745.3 expression in the LNCaP androgen-sensitive human prostate adenocarcinoma cell line. In addition, overexpression of AC016745.3 inhibits the proliferation and migration of PCa cells, and suppresses the expression of AR target genes. This research also demonstrates that the protein NONO interacts with AR and functions as an AR co-activator, promoting AR transcriptional activity. Furthermore, using RNA immunoprecipitation (RIP)-PCR experiments, the study demonstrates that both NONO and AR can bind AC016745.3. Moreover, cell phenotypic experiments reveal that NONO can promote cellular proliferation and migration, and that AC016745.3 can partially antagonize the pro-oncogenic functions of NONO in PCa cells. In summary, the results indicate that AC016745.3 can bind NONO, suppressing its ability to promote AR-dependent transcriptional activity. Furthermore, DHT-dependent suppression of AC016745.3 expression can enhance NONO’s promotion effect on AR. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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17 pages, 5384 KiB

Open AccessArticle

Comprehensive Characterization of Androgen-Responsive circRNAs in Prostate Cancer

by Zhe Kong, Yali Lu, Xuechao Wan, Jun Luo, Dujian Li, Yan Huang, Chenji Wang, Yao Li and Yaoting Xu

Life 2021, 11(10), 1096; https://doi.org/10.3390/life11101096 - 15 Oct 2021

Cited by 4 | Viewed by 1957

Abstract

The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5

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The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5

^{'}

to 3

^{'}

polarity or 3

^{'}

poly (A), play an important role in multiple diseases. However, the potential roles of androgen-responsive circRNAs in prostate cancer remain unclear. In this study, we identified 3237 androgen-responsive circRNAs and 1954 androgen-responsive mRNAs after dihydrotestosterone (DHT) stimulation using microarray. Among them, the expression of 1296 androgen-responsive circRNAs was consistent with that of their parent genes, and we thought AR might regulate the expression of these circRNAs at the transcriptional level. In addition, 1941 circRNAs expression was not consistent with their parent genes, and we speculated that AR may regulate the expression of those circRNAs at the posttranscriptional level through affecting alternative splicing. Analyzing the androgen-responsive circRNAs regulated at the posttranscriptional level, we identified two key RNA binding proteins (RBPs), WTAP and TNRC6, using the circInteractome database, which may play important role in the biogenesis of androgen-responsive circRNAs. Furthermore, we explored the potential biological functions and predicted the molecular mechanisms of two dysregulated circRNAs (circNFIA and circZNF561) in prostate cancer. In this study, we revealed that circNFIA was upregulated in prostate cancer tissues and plasma samples from patients with prostate cancer; circNFIA may play an oncogenic role in prostate cancer. In contrast, circZNF561 was downregulated and may act as a tumor suppressor in prostate cancer. Our results suggest that androgen-responsive circRNAs might regulate the progression of prostate cancer and could be novel diagnostic biomarkers. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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15 pages, 3731 KiB

Open AccessArticle

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

by Tiziana Siciliano, Ingo H. Simons, Alicia-Marie K. Beier, Celina Ebersbach, Cem Aksoy, Robert I. Seed, Matthias B. Stope, Christian Thomas and Holger H. H. Erb

Life 2021, 11(9), 874; https://doi.org/10.3390/life11090874 - 25 Aug 2021

Cited by 7 | Viewed by 2794

Abstract

Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups. Androgen-dependent LNCaP and LAPC4 cells as well as androgen-independent C4-2 cells were treated with distinct concentrations of antiandrogens. Androgen receptor (AR)-mediated gene transactivation was determined using qPCR. Cell viability was measured by WST1 assay. Protein stability and AR localization were determined using western blot. Response to the tested antiandrogens across cellular backgrounds differed primarily in AR-mediated gene transactivation and cell viability. Antiandrogen treatment in LNCaP and LAPC4 cells resulted in AR protein level reduction, whereas in C4-2 cells marginal decreased AR protein was observed after treatment. In addition, AR downregulation was already detectable after 4 h, whereas reduced AR-mediated gene transactivation was not observed before 6 h. None of the tested antiandrogens displayed an advantage on the tested parameters within one cell line as opposed to the cellular background, which seems to be the primary influence on antiandrogen efficacy. Moreover, the results revealed a prominent role in AR protein stability. It is one of the first events triggered by antiandrogens and correlated with antiandrogen efficiency. Therefore, AR stability may surrogate antiandrogen response and may be a possible target to reverse antiandrogen resistance. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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15 pages, 2272 KiB

Open AccessArticle

Differential Expression of the Androgen Receptor, Splice Variants and Relaxin 2 in Renal Cancer

by Joanna Bialek, Maria Piwonka, Felix Kawan, Paolo Fornara and Gerit Theil

Life 2021, 11(8), 731; https://doi.org/10.3390/life11080731 - 22 Jul 2021

Cited by 4 | Viewed by 1842

Abstract

Background: The role of the androgen receptor (AR) in renal cell carcinoma (RCC) is unclear. We aimed to analyze the expression of AR and its splice variants (SVs) and their correlation with relaxin 2 (RLN2) and cytokines in RCC. Methods: We investigated the expression of RLN2 and AR variants in 25 clear cell RCC (ccRCC) and 9 papillary (pRCC) tumor tissues and the corresponding controls using quantitative PCR and serum RLN2, testosterone and cytokine levels in matched samples using ELISA and chemiluminescent immunometric assay, respectively. Results: ccRCC tissues but not pRCC tissues more frequently expressed AR and the SVs than did normal tissues. All pRCC samples expressed more AR than did ccRCC samples. The highest expression of all AR variants except AR-V12 was found in low-stage tumors, with dominant expression of AR-V7. In males in the ccRCC cohort, the expression of AR-FL, AR-V1 and AR-V3 was significantly correlated with that of RLN2. The secretion pattern of proinflammatory IL-6 was higher in ccRCC than in pRCC. Conclusions: The results highlight additional molecular differences between ccRCC and pRCC, suggesting the influence of external factors on the whole kidney or genetic predispositions to developing certain types of renal cancer, and may support further pathological analysis and studies of targeted hormone therapy. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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12 pages, 7244 KiB

Open AccessArticle

Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation

by Alexey Rayevsky, Dmytro Sirokha, Dariia Samofalova, Dmytro Lozhko, Olexandra Gorodna, Inga Prokopenko and Liudmyla Livshits

Life 2021, 11(7), 659; https://doi.org/10.3390/life11070659 - 06 Jul 2021

Cited by 7 | Viewed by 2941

Abstract

Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, we applied a set of computational approaches for the structural analysis of the ligand-binding domains in a wild-type and mutant AR to evaluate the functional impact of the novel I836S mutation. We revealed that the novel I836S substitution leads to a shorter existence time of the ligand’s gating tunnel and internal cavity, occurring only in the presence of S836 phosphorylation. Additionally, the analysis of phosphorylation of the 836 mutant residues explained the negative impact on AR homodimerization, since monomer surface changes indirectly impacted the binding site. Our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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12 pages, 866 KiB

Open AccessArticle

High Androgen Receptor mRNA Expression Is Associated with Improved Outcome in Patients with High-Risk Non-Muscle-Invasive Bladder Cancer

by Danijel Sikic, Helge Taubert, Ralph M. Wirtz, Johannes Breyer, Markus Eckstein, Veronika Weyerer, Jennifer Kubon, Philipp Erben, Christian Bolenz, Maximilian Burger, Arndt Hartmann, Bernd Wullich, Sven Wach and Bastian Keck

Life 2021, 11(7), 642; https://doi.org/10.3390/life11070642 - 30 Jun 2021

Cited by 3 | Viewed by 1996

Abstract

The role of the androgen receptor (AR) in non-muscle-invasive bladder cancer (NMIBC) remains controversial. We retrospectively analyzed the mRNA expression of AR using RT-qPCR in 95 patients with high-risk NMIBC treated with a bladder-sparing approach and correlated AR with clinical data and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The mRNA expression of AR and KRT5, i.e., the basal-like subtype, was strongly correlated (rs = 0.456; p < 0.001). AR (p = 0.053) and KRT5 (p = 0.029) mRNA expression was negatively correlated with tumor grade. Kaplan–Meier analyses indicated significantly prolonged CSS (p = 0.020) and OS (p = 0.015) and a trend towards longer RFS (p = 0.051) in patients with high AR expression. High KRT5 expression was associated with significantly longer RFS (p = 0.033), CSS (p = 0.029) and OS (p = 0.030), while high KRT20 expression was associated with reduced RFS (p = 0.042). In multivariable analysis, none of the molecular markers was an independent prognostic factor. When performing a substratification with regard to molecular markers and clinicopathological parameters, high AR expression showed improved OS in patients with high KRT20 mRNA expression (p = 0.041). Women showed significantly longer OS in cases with high AR expression (p = 0.011). High AR was associated with significantly improved CSS in males (p = 0.044) and patients with instillation therapy (p = 0.040), while OS was improved regardless of instillation therapy. Younger patients with high AR expression had significantly improved RFS (p = 0.021), CSS (p = 0.014) and OS (p = 0.007). RFS was also improved in patients with high AR and low expression of either KRT5 (p = 0.003) or KRT20 (p = 0.014), but not in patients with high expression of KRT5 or KRT20. In conclusion, high AR mRNA expression is correlated with KRT5 mRNA expression and is associated with an improved outcome in high-risk NMIBC. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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10 pages, 2613 KiB

Open AccessArticle

Comparison of Androgen Receptor, VEGF, HIF-1, Ki67 and MMP9 Expression between Non-Metastatic and Metastatic Stages in Stromal and Tumor Cells of Oral Squamous Cell Carcinoma

by Lovorka Batelja-Vuletic, Cedna Tomasovic-Loncaric, Marcello Ceppi, Marco Bruzzone, Aleksandra Fucic, Karolina Krstanac and Vanja Boras Vucicevic

Life 2021, 11(4), 336; https://doi.org/10.3390/life11040336 - 10 Apr 2021

Cited by 8 | Viewed by 2049

Abstract

Objectives: Oral squamous cell carcinoma (OSCC) is the most common oral malignancy with low survival as it is very often diagnosed at an advanced stage, which is why the accurate profiling of the tumor is essential. The aim of this study was to, for the first time, compare in OSCC the frequency of AR, VEGF, MMP9, HiF1beta and Ki67 between the non-metastatic and metastatic disease. Materials and Methods: In the study, 96 non-metastatic and 91 metastatic OSCC patients were analysed for AR, VEGF, MMP9, HiF1beta and Ki67 levels by immunohistochemistry. Results: All of the tested biomarkers significantly differed between non-metastatic and metastatic disease. A significant association was found between >/=20% AR positive epithelium cells in cytoplasm, Ki67 and VEGF in cancer stroma. Ki67, HiF1beta, VEGF and MMP9 were significantly associated with TNM stages. Conclusion: Our results show for the first time an interplay between AR, VEGF, MMP9, HiF1beta and Ki67 in OSCC which may contribute to better diagnostics and therapy selection. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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Review

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15 pages, 3991 KiB

Open AccessReview

Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

by Steven K. Nordeen, Lih-Jen Su, Gregory A. Osborne, Perry M. Hayman, David J. Orlicky, Veronica M. Wessells, Adrie van Bokhoven and Thomas W. Flaig

Life 2021, 11(9), 884; https://doi.org/10.3390/life11090884 - 27 Aug 2021

Cited by 5 | Viewed by 2334

Abstract

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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9 pages, 1477 KiB

Open AccessReview

A Potential Role and Contribution of Androgens in Placental Development and Pregnancy

by Agata M. Parsons and Gerrit J. Bouma

Life 2021, 11(7), 644; https://doi.org/10.3390/life11070644 - 01 Jul 2021

Cited by 12 | Viewed by 3234

Abstract

Successful pregnancy requires the establishment of a highly regulated maternal–fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal–fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences. Full article

(This article belongs to the Special Issue Androgen Receptor and AR-Related Signaling in Health and Disease)

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