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Gilyazova, I.; Enikeeva, K.; Rafikova, G.; Kagirova, E.; Sharifyanova, Y.; Asadullina, D.; Pavlov, V. Epigenetic Alterations of Bladder Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/46054 (accessed on 23 June 2024).
Gilyazova I, Enikeeva K, Rafikova G, Kagirova E, Sharifyanova Y, Asadullina D, et al. Epigenetic Alterations of Bladder Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/46054. Accessed June 23, 2024.
Gilyazova, Irina, Kadriia Enikeeva, Guzel Rafikova, Evelina Kagirova, Yuliya Sharifyanova, Dilara Asadullina, Valentin Pavlov. "Epigenetic Alterations of Bladder Cancer" Encyclopedia, https://encyclopedia.pub/entry/46054 (accessed June 23, 2024).
Gilyazova, I., Enikeeva, K., Rafikova, G., Kagirova, E., Sharifyanova, Y., Asadullina, D., & Pavlov, V. (2023, June 26). Epigenetic Alterations of Bladder Cancer. In Encyclopedia. https://encyclopedia.pub/entry/46054
Gilyazova, Irina, et al. "Epigenetic Alterations of Bladder Cancer." Encyclopedia. Web. 26 June, 2023.
Epigenetic Alterations of Bladder Cancer
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Bladder cancer (BLCA) is one of the most common types of malignant tumors of the urogenital system in adults. BLCA predominantly originates in the urothelium, which refers to the epithelial tissue lining the inner surface of the bladder and other urinary organs. This characteristic gives rise to urothelial carcinoma, which represents the most prevalent form of bladder cancer, constituting approximately 80–90 percent of all BLCA cases.

bladder cancer epigenetic alterations DNA methylation malignancy histones

1. Introduction

Bladder cancer (BLCA) is a prevalent malignancy affecting the urogenital system in adults. In 2020, there were 573,278 newly diagnosed cases of BLCA, resulting in 212,536 BLCA-related fatalities [1][2]. Systematic smoking is recognized as one of the primary contributors to bladder malignancy [3]. Additionally, occupational exposures and contact with carcinogens play a significant role, accounting for approximately 20–25% of BLCA cases [4]. Advanced age is a known risk factor, as over 90% of patients in the United States are above 55 years old [5]; other risk factors include Caucasian race [6][7] and the use of certain drugs containing phenacetin, cyclophosphamide, or pioglitazone [8][9][10]. The likelihood of developing urinary system neoplasms, particularly BLCA, increases in patients with chronic cystitis, bladder stones, and urinary stasis [11].
BLCA predominantly originates in the urothelium, which refers to the epithelial tissue lining the inner surface of the bladder and other urinary organs. This characteristic gives rise to urothelial carcinoma, which represents the most prevalent form of bladder cancer, constituting approximately 80–90 percent of all BLCA cases. Depending on the ability of the tumor to penetrate the muscular layer, BLCA is classified into non-muscle-invasive (NMIBC) (70% of cases of first detected tumors) and muscle-invasive BLCA (MIBC) (30%) [12]. Currently, the diagnosis of BLCA is based on cystoscopy and cytological examination of urine and additional laboratory and instrumental studies. However, cystoscopy is an invasive study, and voided urine cytology has a low level of sensitivity, so there is a clear need to develop more reliable markers and test systems for detecting the disease with high sensitivity and specificity. Despite receiving 1–3 years of maintenance therapy, patients with NMIBC face a recurrence risk exceeding 50% and a progression risk of 20% within a 5-year period [13]. Although NMIBC exhibits favorable 5-year survival rates (>90%), most patients undergo extensive cystoscopic surveillance and multiple therapeutic interventions, which negatively impact their health-related quality of life [14]. This raises the necessity for the identification of new predictive markers for the disease. Human body fluids (urine, serum, and plasma) are known to contain significant amounts of tumorigenic nucleic acids that can serve as noninvasive biomarkers, particularly useful for early cancer detection, follow-up of patients, and personalization of their treatment. Epigenetic alterations such as DNA methylation, aberrant microRNA expression, long noncoding RNAs, and circular RNA alterations can be detected in the earliest stages of cancer and are quite easily detected in biological fluids even before any clinical signs and morphological changes appear. It should be noted that BLCA is a heterogeneous disease that is difficult to treat, and it has specific genetic and epigenetic features. Early disease detection holds the potential to prevent invasion and metastasis, thereby improving overall survival outcomes for BLCA patients. However, current recommendations do not support screening for BLCA in the general population because of its limited efficacy and high economic costs [13][15]. In such circumstances, it becomes crucial to focus on the development of novel and effective biomarkers for BLCA or the refinement of high-risk groups using genetic, immune, and epigenetic markers. This approach justifies the costs associated with screening by enabling early disease detection and enhancing clinical outcomes [13]. The pursuit of these advancements holds promise for the improved management and prognosis of BLCA.
In human DNA, methylation is a molecular process that targets CpG dinucleotides. Most genes have unmethylated CpGs in their 5′-regulatory region. DNA methyltransferases (DNMTs) catalyze the methylation of these CpGs, thereby inducing silencing of transcription, leading to suppression of tumor growth and cancer cell invasion.

2. DNA Methylation

DNA methylation is a strong tool for suppressing gene activity. Hyper- and hypomethylated DNA sites are identified in BLCA and precancerous lesions. DNA methylation status can be assessed from cell-free DNA fragments and tumor cells excreted with urine. A significant predominance of methylated genes such as APC and CCND2 (cyclin D2) has been detected in BLCA compared to benign cases. Hypermethylation of individual genes including GSTP1, APC, and RARB2 has been identified in patients with urothelial BLCA [16].
It is important that this inverse correlation has been clearly shown only for methylation in the promoter regions but not in the coding part of the genes. Methyl groups do not have influence on base conjugation, but they can affect the protein–DNA interaction by acting in the main groove [17]. The identification of CpG residues within the promoters of certain tumor suppressor genes linked to bladder cancer (BLCA) has spurred extensive research into the role of methylation in gene suppression. Hypermethylation occurring in the promoter regions of 50 genes has been associated with transcriptional silencing, offering an alternative mechanism for suppressing gene expression in addition to gene deletion or mutation. Notably, hypermethylation of the promoter region of the p16INK4A gene has been observed in patients with superficial transitional cell carcinomas, suggesting its potential involvement as an early event in the pathogenesis of transitional cell carcinomas [18]. In particular, a high frequency of mutations has been found in the KMT2D gene (also known as MLL2) and in the KDM6A gene (also known as UTX), which encode histone H3 lysine 4 methyltransferase and histone lysine demethylase, respectively [19][20][21]. However, the most studied epigenetic mechanism is DNA methylation [22]. Comparing methylation patterns, Wolff et al. found global hypomethylation in NMIBC, whereas hypermethylation was more frequent in other tumors, which supports the concept that DNA methylation plays an important role in the formation and aggressiveness of BLCA, being a putative target for anticancer therapy [23].
Methylated genes, including SFRP1, SOX9, FHIT, CDH1, PMF1, RUNX3, LAMC2, and RASSF1A, cannot only be considered as biomarkers but are also associated with poor clinical outcomes in patients with BLCA [24]. This suggests the potential utility of DNA methylation as a prognostic marker. Through univariate and multivariate Cox regression analysis, genes with differential DNA methylation can be employed as prognostic biomarkers for BLCA. By utilizing this prognostic model, patients can be stratified into high- or low-risk groups. Assessing the methylation status of these genes allows for the evaluation of patient survival [25].
In urine samples from 108 UCB patients and 100 age- and gender-matched controls, the methylation levels of FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST, and ZIC1 markers were quantitatively assessed using methylation-specific qPCR in urine sediment. All nine urinary methylation markers (FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST, and ZIC1) exhibited significantly higher methylation levels in BLCA patients compared to the control group (p < 0.001) [26]. Importantly, the methylation alterations detected in urine sediment samples resemble those observed in tumor tissues [27][28].
After performing sequential clustering to identify DNA methylation subgroups in BLCA, differences between subgroups, including DNA methylation levels, were examined. The results revealed significant prognostic differences among the four subgroups of molecular subtypes of BLCA. Thus, the study allowed for the identification of molecular subtypes of BLCA based on DNA methylation and determination of their prognostic characteristics. These findings can be valuable for clinicians in predicting patient survival and making treatment decisions [29].
Analysis of the expression of 15 DNA methylation regulators in 985 samples from six independent cohorts of BLCA revealed alterations in DNA methylation regulators at a frequency of 12.62% [30]. The MBD1 gene had the highest frequency of alterations in BLCA, indicating its involvement in oncogenesis. The frequency of changes in DNMT1, DNMT3A, and DNMT3B genes was also 2%. Co-mutations were observed in several DNA methylation regulators, including NTHL1, MBD3, MECP2, UHRF2, and ZBTB33, despite their functional differences.
Analysis of DNA methylation regulators revealed three different clusters (A, B, and C) based on their expression levels with different patient survival rates. Each cluster exhibited significantly different characteristics of the tumor microenvironment [30].
Analysis of DNA methylation profiles in the peripheral blood of 603 patients, who were part of a population cohort in New Hampshire, with NMIBC and investigating the association between methylation profiles and patient outcomes, particularly focusing on the methylation-driven neutrophil-to-lymphocyte ratio (mdNLR), revealed that increased mdNLR increases the risk of recurrence-free survival (RFS) in patients with NMIBC. For patients with high-risk recurrence of NMIBC, intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the standard treatment to induce an immune response against remaining BLCA cells after surgery, thus the immune profile of the blood represents a potential prognostic factor [31]. Thus, DNMT inhibitors are being considered as a promising therapeutic strategy for BLCA [32].
Some of these inhibitors, such as 5-azacytidine and decitabine, have already been approved for the treatment of specific types of blood cancer. However, these inhibitors have limitations that restrict their application. Combining them with chemotherapy or immune checkpoint inhibitors can enhance their effectiveness. Current research includes both laboratory and clinical studies, investigating the effects of DNMT inhibition on DNA methylation in the context of BLCA. This research direction presents new perspectives in the treatment of BLCA and may lead to the development of alternative or adjunctive therapeutic strategies [32].
A number of epigenetic mechanisms are disrupted in the early stages of BLCA development and progression [22]. For example, mutations in EP300 and CREBBP, two chromatin remodeling genes, lead to inactivation of the histone acetyltransferase domain complex, which subsequently changes the chromatin conformation. Furthermore, gene expression associated with the loss of histone acetyltransferase activity is associated with more aggressive bladder tumors [33]. Interestingly, mutations in histone-modifying genes have been observed in 89% of lesions [34].

3. Histone Modifications

The fundamental structural units of chromatin, the protein–DNA complex, are nucleosomes, consisting of negatively charged DNA wrapped around histones, which are positively charged proteins. Histones can undergo posttranslational modifications (PTMs) such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation, each of which plays a role in gene regulation and other mechanisms such as DNA repair, cell division, and cell differentiation [35]. PTMs of histones play a significant role in the pathogenesis of tumors, contributing to their proliferation and development [36]. Most types of invasive BLCA exhibit at least one histone modification [31].
Proteomic analysis of major histones in BLCA cell line 5637 revealed that PTMs vary in frequency at different histone sites. Some histone sites exclusively displayed acetylation without methylation, while others exhibited only monomethylation without acetylation. Additionally, it was found that certain histone regions simultaneously exhibited multiple distinct PTMs [37].
Among all histones, methylation of histone H3 has been extensively studied. This histone modification is of great interest because of its ability to influence gene expression, either activating genes (e.g., H3K4me3 and H3K36me3) or repressing them (e.g., H3K27me3 and H3K9me3) [36]. These modifications are mediated by mutations in the EZH2 gene (an oncogene encoding a histone methyltransferase, also known as HMT) that trimethylates H3K27, leading to the silencing of the tumor-suppressor gene E-cadherin [38]. Furthermore, the modification of H3 protein is associated with a high degree of malignancy in invasive cancer. Chromatin-remodeling gene mutations are more frequently observed in BLCA than in any other cancer type (ARID1A, KDM6A, CHD6, or MLL) [35].
Different types of histone PTMs have varying effects on carcinogenesis. For instance, the PTM H3K4me1 correlates with advanced stages of MIBC and unfavorable survival outcomes [36]. H3K4me3 induces DNA replication and repair defects, increases chromatin instability, and serves as a potential biomarker for high-grade BLCA, as well as luminal papillary and basal squamous subtypes of BLCA. PTM H3K4me1/2 causes DNA replication and cell-cycle disturbances, induces cell invasion and migration, and is associated with recurrence and therapy resistance. PTM H3K9me2 promotes the development of NMIBC and possesses immunomodulatory effects. PTM H3K9me3 and H3K36me3 contribute to the development of higher-grade BLCA. PTM H3K27me2/3 promotes tumor development and progression in BLCA and predicts progression and recurrence in NMIBC. PTM H3K27me3 induces immune evasion of tumors, activates pro-inflammatory pathways, and leads to dysregulation of gene expression associated with cellular identity [36].
Various patterns of histone methylation have been identified in the context of MBIC and NMIBC, indicating the potential for distinct responses to epigenetic therapy among patients in these subgroups. Consequently, there is a pressing need to evaluate PTMs of histones for predicting responses to such epigenetic modulators. Investigation has revealed that the methyltransferase G9a is overexpressed in BLCA, and its inhibition has been demonstrated to impact cell survival through the regulation of the AMPK-mTOR pathway. Additionally, it has been reported that the interaction between G9a and DNA methyltransferase 1 (DNMT1) leads to the suppression of transcription of target genes. Furthermore, this enzyme can interact with EZH2, causing genetic inactivation of specific genes and, thereby, presenting a potential target for the treatment of progressive metastatic BLCA [36].
The diverse profiles of histone modifications are believed to reflect subtypes of luminal and basal cells. Specifically, one cluster, H3K4me1, was exclusively found in basal tumors, suggesting that the (in)activation of enhancers may contribute to the differences observed between subtypes of MIBC [39].
DNA methylation and PTMs, which dictate gene expression regulation, are reversible, making them potential targets for therapeutic intervention [40]. Inhibiting enzymes can reverse gene silencing and restore the expression of tumor-suppressor genes [31]. For instance, low concentrations of nZnO promote late-stage apoptosis of BLCA T24 cells and suppress cell invasion and migration. These antitumor effects may be attributed to elevated levels of RUNX3 because of reduced occupancy of H3K27me3 at the RUNX3 promoter, as well as decreased levels of histone methyltransferase EZH2 and H3K27 trimethylation [41].
Another potential mechanism to influence histone PTMs is through the epigenetic regulation of small noncoding RNAs (sncRNAs), such as microRNAs (miRNAs), which have an impact on histone modification regulation. In some cases, sncRNAs can target components of the histone-modification machinery, including histone methyltransferases and demethylases, thereby influencing the levels and patterns of histone modifications. This interaction between sncRNAs and histone modifications represents a regulatory mechanism that can modulate gene expression and cellular processes, including those associated with cancer development and progression [36]. Epigenetic alterations play a crucial role in the pathogenesis and progression of BLCA. Indeed, BLCA arises from multiple epigenetic events that inactivate known tumor suppressors through DNA methylation and histone modification [42].

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