Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer

Abstract

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.

MicroRNA‐494‐3p facilitates the progression of bladder cancer by mediating the KLF9/RGS2 axis

“…miRNA usually possesses the capacity of binding multiple target genes 25 . In mammalian cells, it is universally acknowledged that miRNAs are at least partially complementary to the 3′‐UTR of the target mRNA molecule to mediate the target gene expression at the posttranscriptional level 26 . KLF9 belongs to the KLF transcriptional factor family, and it was reported to participate in the progression of ovarian cancer and BC 27,28 .…”

“…25 In mammalian cells, it is universally acknowledged that miRNAs are at least partially complementary to the 3 0 -UTR of the target mRNA molecule to mediate the target gene expression at the posttranscriptional level. 26 KLF9 belongs to the KLF transcriptional factor family, and it was reported to participate in the progression of ovarian cancer and BC. 27,28 Yang et al reported that KLF9 had lower expression in BC and was a targeted gene of miR-17-5p.…”

Molecular Oncology of Bladder Cancer from Inception to Modern Perspective

“…Along with the genomic/transcriptomic approaches, metabolomic analyses of urine specimens, the availability of the Human Metabolome Database, and the bulk epigenome analyses approaches have identified altered pathways in BC, some of which are likely associated with bladder carcinogenesis, growth, and progression to MIBC. Recent reviews describe these discoveries [ 178 , 179 , 180 , 181 , 182 ]. Currently the majority of the “omic” studies at all levels (gene, epigenetic, transcript, protein, metabolites) are correlative.…”

Epigenetic alterations in urothelial bladder cancer associated with disease outcomes

“…5,6 To date, methylation signatures have been applied as cancer biomarkers due to their dynamic behavior across tumor stage and grade, stability between individuals and consistency within tissue specificity. 7,8 Some have already been identified in bladder tumor tissue and liquid biopsy samples. [9][10][11][12] Recently, an investigation conducted by our group revealed that the DNA methylation pattern of seven new genes was linked to an abnormal gene expression in breast tumor tissue samples and related to clinical outcomes.…”

“…Epigenetic dysregulation, namely, DNA methylation, refers to the mechanisms by which the cell phenotype can be reversibly affected without altering the DNA sequence 5,6 . To date, methylation signatures have been applied as cancer biomarkers due to their dynamic behavior across tumor stage and grade, stability between individuals and consistency within tissue specificity 7,8 . Some have already been identified in bladder tumor tissue and liquid biopsy samples 9–12 …”