Abstract
Simple SummaryCurrent diagnostic and follow-up methods for the clinical management of bladder cancer (BC) have limitations, and there is an urgent unmet need for non-invasive biomarkers for this highly prevalent disease. Furthermore, personalized treatments for patients could improve their quality of life and overall survival. The aim of this article is to review the literature in this area, with a primary focus on metabolic and epigenetic biomarkers of BC, as well as the targeted therapies discovered to date. We show the dynamic biological interplay established between epigenomics and metabolomics in the context of BC. These findings may be useful both for researchers and physicians in the field of BC, and could facilitate clinical decision-making regarding patients at diagnosis, prognosis, monitoring, or treatment.Bladder cancer (BC) represents a clinical, social, and economic challenge due to tumor-intrinsic characteristics, limitations of diagnostic techniques and a lack of personalized treatments. In the last decade, the use of liquid biopsy has grown as a non-invasive approach to characterize tumors. Moreover, the emergence of omics has increased our knowledge of cancer biology and identified critical BC biomarkers. The rewiring between epigenetics and metabolism has been closely linked to tumor phenotype. Chromatin remodelers interact with each other to control gene silencing in BC, but also with stress-inducible factors or oncogenic signaling cascades to regulate metabolic reprogramming towards glycolysis, the pentose phosphate pathway, and lipogenesis. Concurrently, one-carbon metabolism supplies methyl groups to histone and DNA methyltransferases, leading to the hypermethylation and silencing of suppressor genes in BC. Conversely, α-KG and acetyl-CoA enhance the activity of histone demethylases and acetyl transferases, increasing gene expression, while succinate and fumarate have an inhibitory role. This review is the first to analyze the interplay between epigenome, metabolome and cell signaling pathways in BC, and shows how their regulation contributes to tumor development and progression. Moreover, it summarizes non-invasive biomarkers that could be applied in clinical practice to improve diagnosis, monitoring, prognosis and the therapeutic options in BC.
Highlights
Bladder cancer (BC) is the second most common urological malignancy after prostate cancer, and its development has previously been shown to be strongly related to smoking, schistosomiasis infection, and occupational exposure to certain chemicals [1,2]
MiRNAs have been shown to target key enzymes involved in aerobic glycolysis, the TCA cycle and lipid metabolism [185], and control the aberrant expression of central epigenetic enzymes, such as enhancer of zeste homolog 2 (EZH2), and their expression can even be affected as a consequence of the hypermethylation of the gene that encodes them by both DNA methyltransferases (DNMT) and histone methyltransferases (HMTs) [186]
EZH2 interacts with chromatin remodelers such as G9a and DNMTs, and with hypoxiainducible factors (HIFs), MYC, and oncogenic signaling cascades, such as PI3K/Akt, to regulate metabolic reprogramming
Summary
BC is the second most common urological malignancy after prostate cancer, and its development has previously been shown to be strongly related to smoking, schistosomiasis infection, and occupational exposure to certain chemicals [1,2]. Epigenetic mechanisms regulate metabolic gene expression to offer adaptive responses to rapidly changing environmental conditions and prolong tumor cell survival [20,21] Understanding this dynamic relationship between metabolism and epigenetics and how they may be dysregulated in cancer is crucial to identify novel therapeutic targets and biomarkers. The review presented here is, to our knowledge, the first that analyzes the interplay among epigenomics, metabolomics, and cell signaling pathways in the context of BC It provides an overview of the complex interplay between these biochemical and molecular processes and highlights the metabolites, metabolic enzymes, miRNAs, and lncRNAs postulated as emerging clinical biomarkers and therapeutic targets in the context of BC. This review integrates the current knowledge about the pathology of BC and may help to improve clinical decision-making regarding BC patients, whether at the level of diagnosis, prognosis, monitoring, or treatment
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