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Epigenetics of Urological Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 48765

Special Issue Editors

Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, Germany
Interests: Urothelial carcinoma; Cancer epigenetics; DNA methylation; Chromatin regulators; Epigenetic drugs; Endogenous retroelements
Department of Clinical Medicine, Aarhus University & Department of Molecular Medicine, Aarhus University Hospital, Denmark
Interests: Prostate cancer; molecular diagnostics; omics; translational cancer research; cancer epigenetics; DNA methylation; cancer biomarkers

Special Issue Information

Dear Colleagues,

During embryonic development and in tissue homeostasis, a diversity of distinct cellular phenotypes is generated from the same genome by epigenetic mechanisms like DNA methylation, histone modifications and chromatin remodeling. In the same manner, epigenetic mechanisms establish the aberrant phenotype of tumor cells from a genome with - often multifarious–genetic alterations. Moreover, epigenetic regulators themselves are mutated in many cancers, including in urological malignancies. An altered epigenome is therefore an essential characteristic of basically all malignant tumors. Thus, elucidating the causes and consequences of altered epigenomes is an essential prerequisite to understanding cancer development and progression. In addition, the epigenomes of cancer cells offer specific targets for therapy (for instance, certain enzymes modifying histones or DNA), and furthermore provide molecular biomarkers for detection, prognosis and prediction of response to therapy.

The major urological cancers comprise prostate adenocarcinoma, urinary bladder (or upper urinary tract) carcinoma, renal cell carcinoma, testicular cancer and penile carcinoma, in this order of incidence, and each with various histological and molecular subtypes. Genomic changes in these cancers are becoming comprehensively characterized through e.g. large-scale genomic sequencing initiatives. Molecular profiling of epigenetic changes in these cancers has also begun. However, this is even more demanding given the many layers of epigenetic regulation (DNA methylation, histones, chromatin, non-coding RNAs).

In this Special Issue, we invite authors to present new results, ideas and approaches on the “Epigenetics of Urological Cancers” in order to answer some of the many open questions in this field with the aims of deepening the understanding of the pathogenesis, improving the diagnostics and augmenting the therapy of these malignancies. We would like to invite original research papers on pathogenetic mechanisms, as well as those with a translational perspective, aiming at bridging the gap between basic and clinical research for urological cancer epigenetics.

Prof. Wolfgang A. Schulz
Prof. Karina Dalsgaard Sorensen
Guest Editors

Manuscript Submission Information

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Keywords

  • Prostate cancer
  • Bladder cancer
  • Renal cancer
  • Testis cancer
  • Penile cancer
  • Epigenetics
  • Epigenome
  • Chromatin
  • DNA methylation
  • Histone modifications
  • Chromatin remodeling
  • Long non-coding RNA (nuclear)
  • Epigenetic biomarkers
  • Epigenetic drugs

Published Papers (10 papers)

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Editorial

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4 pages, 467 KiB  
Editorial
Epigenetics of Urological Cancers
by Wolfgang A. Schulz and Karina D. Sørensen
Int. J. Mol. Sci. 2019, 20(19), 4775; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194775 - 26 Sep 2019
Cited by 9 | Viewed by 2045
Abstract
The major urological cancers comprise prostate adenocarcinoma, urinary bladder (or upper urinary tract) carcinoma, renal cell carcinoma, testicular cancer and penile carcinoma, in this order of incidence, each with various histological and molecular subtypes [...] Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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Research

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18 pages, 3154 KiB  
Article
Characterization of Histone Deacetylase Expression Within In Vitro and In Vivo Bladder Cancer Model Systems
by Jenna M. Buckwalter, Wilson Chan, Lauren Shuman, Thomas Wildermuth, Justine Ellis-Mohl, Vonn Walter, Joshua I. Warrick, Xue-Ru Wu, Matt Kaag, Jay D. Raman and David J. DeGraff
Int. J. Mol. Sci. 2019, 20(10), 2599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102599 - 27 May 2019
Cited by 14 | Viewed by 4727
Abstract
Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas [...] Read more.
Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas (TCGA). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis was used to determine the expression status of Class I and II HDACs in ten human BC cell lines, while qRT-PCR was used to determine HDAC expression in 24 human tumor specimens. The TCGA cohort consists of 408 muscle invasive BC (MIBC) clinical samples and analysis of this data set identified expression of HDAC4 and -9 as being associated with basal–squamous disease. These findings agree with qRT-PCR results identifying increased expression of HDAC4, -7, and -9 in basal BC cell lines (p < 0.05; Kruskal–Wallis test) and in clinical specimens with invasive bladder cancer (not statistically significant). We also observed increased expression in Hdac4, -7, and -9 in commonly used BC mouse models. Here, we identify suitable preclinical model systems for the study of HDACs, and show increased expression of Class IIa HDACs, specifically HDAC4 and HDAC9, in basal BC cell lines and in invasive clinical specimens. These results suggest this class of HDACs may be best suited for targeted inhibition in patients with basal BC. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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18 pages, 6417 KiB  
Article
HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long-Term Proliferation but Can Promote Epithelial-to-Mesenchymal Transition
by Ananda Ayyappan Jaguva Vasudevan, Michèle J. Hoffmann, Michael L. C. Beck, Gereon Poschmann, Patrick Petzsch, Constanze Wiek, Kai Stühler, Karl Köhrer, Wolfgang A. Schulz and Günter Niegisch
Int. J. Mol. Sci. 2019, 20(9), 2135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092135 - 30 Apr 2019
Cited by 14 | Viewed by 3857
Abstract
Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in [...] Read more.
Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in UC cell lines suggesting a possible tumor-suppressive function. We therefore characterized the effects of stable HDAC5 expression in four UC cell lines (RT112, VM-Cub-1, SW1710 and UM-UC-3) with different phenotypes reflecting the heterogeneity of UC, by assessing proliferation, clonogenicity and migration ability. Further, we detailed changes in the proteome and transcriptome by immunoblotting, mass spectrometry and RNA sequencing analysis. We observed that HDAC5 overexpression in general decreased cell proliferation, but in one cell line (VM-Cub-1) induced a dramatic change from an epitheloid to a mesenchymal phenotype, i.e., epithelial-mesenchymal transition (EMT). These phenotypical changes were confirmed by comprehensive proteomics and transcriptomics analyses. In contrast to HDAC5, overexpression of HDAC4 exerted only weak effects on cell proliferation and phenotypes. We conclude that overexpression of HDAC5 may generally decrease proliferation in UC, but, intriguingly, may induce EMT on its own in certain circumstances. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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21 pages, 2694 KiB  
Article
Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer
by Marianne T. Bjerre, Siri H. Strand, Maibritt Nørgaard, Helle Kristensen, Anne KI Rasmussen, Martin Mørck Mortensen, Jacob Fredsøe, Peter Mouritzen, Benedicte Ulhøi, Torben Ørntoft, Michael Borre and Karina D. Sørensen
Int. J. Mol. Sci. 2019, 20(5), 1173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051173 - 07 Mar 2019
Cited by 27 | Viewed by 3951
Abstract
Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in [...] Read more.
Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75–94%) and specificity (84–100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24–3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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12 pages, 1496 KiB  
Article
5hmC Level Predicts Biochemical Failure Following Radical Prostatectomy in Prostate Cancer Patients with ERG Negative Tumors
by Gitte Kristensen, Siri H. Strand, Martin Andreas Røder, Kasper Drimer Berg, Birgitte Grønkær Toft, Søren Høyer, Michael Borre, Karina Dalsgaard Sørensen and Klaus Brasso
Int. J. Mol. Sci. 2019, 20(5), 1025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051025 - 27 Feb 2019
Cited by 4 | Viewed by 2934
Abstract
This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP [...] Read more.
This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5–10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2–2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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Review

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20 pages, 885 KiB  
Review
DNA-Methylation-Based Detection of Urological Cancer in Urine: Overview of Biomarkers and Considerations on Biomarker Design, Source of DNA, and Detection Technologies
by Louise Katrine Larsen, Guro Elisabeth Lind, Per Guldberg and Christina Dahl
Int. J. Mol. Sci. 2019, 20(11), 2657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20112657 - 30 May 2019
Cited by 44 | Viewed by 5002
Abstract
Changes in DNA methylation have been causally linked with cancer and provide promising biomarkers for detection in biological fluids such as blood, urine, and saliva. The field has been fueled by genome-wide characterization of DNA methylation across cancer types as well as new [...] Read more.
Changes in DNA methylation have been causally linked with cancer and provide promising biomarkers for detection in biological fluids such as blood, urine, and saliva. The field has been fueled by genome-wide characterization of DNA methylation across cancer types as well as new technologies for sensitive detection of aberrantly methylated DNA molecules. For urological cancers, urine is in many situations the preferred “liquid biopsy” source because it contains exfoliated tumor cells and cell-free tumor DNA and can be obtained easily, noninvasively, and repeatedly. Here, we review recent advances made in the development of DNA-methylation-based biomarkers for detection of bladder, prostate, renal, and upper urinary tract cancers, with an emphasis on the performance characteristics of biomarkers in urine. For most biomarkers evaluated in independent studies, there was great variability in sensitivity and specificity. We discuss issues that impact the outcome of DNA-methylation-based detection of urological cancer and account for the great variability in performance, including genomic location of biomarkers, source of DNA, and technical issues related to the detection of rare aberrantly methylated DNA molecules. Finally, we discuss issues that remain to be addressed to fully exploit the potential of DNA-methylation-based biomarkers in the clinic, including the need for prospective trials and careful selection of control groups. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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31 pages, 5929 KiB  
Review
Epigenetic Control of Gene Expression in the Normal and Malignant Human Prostate: A Rapid Response Which Promotes Therapeutic Resistance
by Fiona M. Frame and Norman J. Maitland
Int. J. Mol. Sci. 2019, 20(10), 2437; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102437 - 17 May 2019
Cited by 7 | Viewed by 4326
Abstract
A successful prostate cancer must be capable of changing its phenotype in response to a variety of microenvironmental influences, such as adaptation to treatment or successful proliferation at a particular metastatic site. New cell phenotypes emerge by selection from the large, genotypically heterogeneous [...] Read more.
A successful prostate cancer must be capable of changing its phenotype in response to a variety of microenvironmental influences, such as adaptation to treatment or successful proliferation at a particular metastatic site. New cell phenotypes emerge by selection from the large, genotypically heterogeneous pool of candidate cells present within any tumor mass, including a distinct stem cell-like population. In such a multicellular model of human prostate cancer, flexible responses are primarily governed not only by de novo mutations but appear to be dominated by a combination of epigenetic controls, whose application results in treatment resistance and tumor relapse. Detailed studies of these individual cell populations have resulted in an epigenetic model for epithelial cell differentiation, which is also instructive in explaining the reported high and inevitable relapse rates of human prostate cancers to a multitude of treatment types. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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36 pages, 3188 KiB  
Review
Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer
by Aikaterini F. Giannopoulou, Athanassios D. Velentzas, Eumorphia G. Konstantakou, Margaritis Avgeris, Stamatia A. Katarachia, Nikos C. Papandreou, Nikolas I. Kalavros, Vassiliki E. Mpakou, Vassiliki Iconomidou, Ema Anastasiadou, Ioannis K. Kostakis, Issidora S. Papassideri, Gerassimos E. Voutsinas, Andreas Scorilas and Dimitrios J. Stravopodis
Int. J. Mol. Sci. 2019, 20(6), 1291; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061291 - 14 Mar 2019
Cited by 43 | Viewed by 5965
Abstract
Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite [...] Read more.
Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. “Acetyl-chromatin” homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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19 pages, 915 KiB  
Review
Epigenetic Mechanisms Influencing Epithelial to Mesenchymal Transition in Bladder Cancer
by Sara Monteiro-Reis, João Lobo, Rui Henrique and Carmen Jerónimo
Int. J. Mol. Sci. 2019, 20(2), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020297 - 13 Jan 2019
Cited by 29 | Viewed by 5104
Abstract
Bladder cancer is one of the most incident neoplasms worldwide, and its treatment remains a significant challenge, since the mechanisms underlying disease progression are still poorly understood. The epithelial to mesenchymal transition (EMT) has been proven to play an important role in the [...] Read more.
Bladder cancer is one of the most incident neoplasms worldwide, and its treatment remains a significant challenge, since the mechanisms underlying disease progression are still poorly understood. The epithelial to mesenchymal transition (EMT) has been proven to play an important role in the tumorigenic process, particularly in cancer cell invasiveness and metastatic potential. Several studies have reported the importance of epigenetic mechanisms and enzymes, which orchestrate them in several features of cancer cells and, specifically, in EMT. In this paper, we discuss the epigenetic enzymes, protein-coding and non-coding genes, and mechanisms altered in the EMT process occurring in bladder cancer cells, as well as its implications, which allows for improved understanding of bladder cancer biology and for the development of novel targeted therapies. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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28 pages, 3300 KiB  
Review
Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic
by João Lobo, Ad J. M. Gillis, Carmen Jerónimo, Rui Henrique and Leendert H. J. Looijenga
Int. J. Mol. Sci. 2019, 20(2), 258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020258 - 10 Jan 2019
Cited by 90 | Viewed by 10262
Abstract
Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility [...] Read more.
Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogenesis, referred to as ‘genvironment’. Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. In addition, it allows for identification of clinically relevant and informative biomarkers both for diagnosis and follow-up of individual patients. The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented. Full article
(This article belongs to the Special Issue Epigenetics of Urological Cancers)
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