Alterations of Chromatin Regulators in the Pathogenesis of Urinary Bladder Urothelial Carcinoma
Department of Urology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(23), 6040; https://doi.org/10.3390/cancers13236040
Submission received: 25 October 2021
/
Revised: 29 November 2021
/
Accepted: 29 November 2021
/
Published: 30 November 2021
(This article belongs to the Special Issue Feature Paper from Journal Reviewers)
Simple Summary
Urinary 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.
Abstract
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.
