Methyltransferases in apoptosis and cancer

Abstract

Chromatin is regarded as the primary cause of epigenetic silencing. In addition DNA methyltransferases and DNA methylation play an important role in the regulation of gene expression. DNA methylation is catalyzed by DNA methyltransferases, which create a site-and tissue-specific DNA methylation pattern during development. The Profiling of these DNA methylation patterns in tumors is believed to provide tools for grading and typing of different cancers. One methylation-maintenance (DNMT1) and two de novo methyltransferases (DNMT3A, DNMT3B) are well characterized. Methyltransferases play their epigenetic concert in crucial positions and intersections of pro- and antiapoptotic pathways: to date, several downstream signal targets have been identified, e. g. p16, DAP-kinase, p14ARF, Apaf1, RARs, caspase 8, and the pro-apoptotic caspase TMS1. These apoptosis-relevant genes are frequently associated with hypermethylation and loss of function in human neoplasia. Transcription factor p53 is one of the major candidates linking alterations in chromatin structure, methyltransferase expression and apoptotic cell death. At present, inactivation of DNMTs using specific inhibitors or antisense strategies is only of limited clinical efficacy. In future, epigenetic processes such as chromatin alteration and DNA methylation will provide promising new targets for therapeutic interventions.