DNA Methylation and Chromatin Regulators in Bladder Cancer

Pronounced changes in epigenetic regulation contribute crucially to bladder cancer development and progression. DNA methylation patterns are severely disturbed, with—often extensive—hypomethylation across the genome and less pervasive, but significant local hypermethylation. Hypomethylation is thought to contribute to genomic instability, whereas hypermethylation may lead to the transcriptional inactivation of specific genes. Moreover, hypermethylation especially of particular genomic regions known as CpG-islands can be used for diagnostic purposes. Several assays for altered methylation are now approved or in clinical trials for detection and surveillance of bladder cancer. Another characteristic of bladder cancer is a very high prevalence of deleterious mutations in chromatin regulator genes, especially in genes that encode components of the trithorax-like COMPASS and chromatin-remodeling SWI/SNF protein complexes or proteins interacting with these. These complexes establish active enhancers in a cell type-specific fashion and are opposed by polycomb complexes that tend to be overactive in bladder cancer. Collectively, changes in these complexes disturb urothelial differentiation and prevent the downregulation of proliferation during terminal differentiation. The high frequency of epigenetic alterations suggests that bladder cancers may respond well to drugs targeting chromatin regulators (known as epidrugs), especially those with enzymatic activity. A large variety of epidrugs has been explored and some promising results have been obtained in preclinical studies, especially in combination with other established therapies. Clinical trials for some drugs are underway.