Abstract
Simple SummaryUrinary bladder cancer is one of the ten major cancers worldwide, with higher incidences in males, in smokers, and in highly industrialized countries. New therapies beyond cytotoxic chemotherapy are urgently needed to improve treatment of these tumors. A better understanding of the mechanisms underlying their development may help in this regard. Recently, it was discovered that a group of proteins regulating the state of chromatin and thus gene expression is exceptionally and frequently affected by gene mutations in bladder cancers. Altered function of these mutated chromatin regulators must therefore be fundamental in their development, but how and why is poorly understood. Here we review the current knowledge on changes in chromatin regulators and discuss their possible consequences for bladder cancer development and options for new therapies.Urothelial carcinoma (UC) is the most frequent histological type of cancer in the urinary bladder. Genomic changes in UC activate MAPK and PI3K/AKT signal transduction pathways, which increase cell proliferation and survival, interfere with cell cycle and checkpoint control, and prevent senescence. A more recently discovered additional category of genetic changes in UC affects chromatin regulators, including histone-modifying enzymes (KMT2C, KMT2D, KDM6A, EZH2), transcription cofactors (CREBBP, EP300), and components of the chromatin remodeling complex SWI/SNF (ARID1A, SMARCA4). It is not yet well understood how these changes contribute to the development and progression of UC. Therefore, we review here the emerging knowledge on genomic and gene expression alterations of chromatin regulators and their consequences for cell differentiation, cellular plasticity, and clonal expansion during UC pathogenesis. Our analysis identifies additional relevant chromatin regulators and suggests a model for urothelial carcinogenesis as a basis for further mechanistic studies and targeted therapy development.
Highlights
The predominant histological subtype is urothelial carcinoma (UC), with squamous cell carcinoma and further rarer entities making up less than 10% of the cases in most populations
High-grade papillary UC and especially carcinoma in situ have a higher risk of progressing to invasive carcinomas
Luminal subtypes are characterized by the expression of markers of urothelial differentiation, including uroplakins and KRT20, which reflect the activity of the transcription factors forkhead box A1 (FOXA1), GATA-binding protein 3 (GATA3), and PPARγ
Summary
Urinary bladder cancer is one of the ten major cancers worldwide with a higher incidence in males, in smokers, and in highly industrialized countries [1]. Telomerase is activated in almost all UC, independent of grade and stage, most frequently by activating mutations in the hTERT promoter These changes would have been considered sufficient to explain the pathogenesis of urothelial cancers. It came as a surprise when mutations in chromatin regulator genes were discovered to represent another consistent alteration in UC [6,7]. Mutations in chromatin regulator genes are even found regularly in papillary UC, which often remain near-diploid and have a comparatively low number of genomic changes. We will attempt to delineate the scope of the alterations in chromatin regulators in UC (Section 2) and to outline possible functional explanations for their high prevalence (Section 3)
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