Epigenetics of neurological cancers

Abstract

Epigenetic mechanisms involving DNA methylation, histone modifications and noncoding RNAs regulate and maintain gene-expression states. Similar to genetic mutations, alterations in epigenetic regulation can lead to uncontrolled cell division, tumor initiation and growth, invasiveness and metastasis. Research in brain cancer, particularly gliomas, has uncovered global and gene-specific DNA hypomethylation, local DNA hypermethylation of gene promoters and the de-regulation of microRNA expression. Understanding epigenetic dysregulation in brain cancers has provided new tools for prognostication, as well as suggesting new approaches to therapy. There is significant interest in new sequencing-based technologies that map genetic and epigenetic alterations comprehensively and at high resolution. These methods are being applied to brain tumors, and will better define the contribution of epigenetic defects to tumorigenesis.

Figure 1. DNA methylation and histone modifications at promoters of normal and cancer cells

(A) At promoters of genes that are actively transcribed, the tails of histone proteins are marked with acetylation and the CpG dinucleotides are unmethylated. (B) Silenced genes can be marked by aberrant methylation of CpG dinucleotides alone, or (C) by histone H3 lysine 27 trimethylation and methylation of CpG dinucleotides or (D) By histone H3 lysine 27 trimethylation in the absence of CpG methylation. Initial reports in cancer cell lines suggest this pattern (D) is found in far fewer genes compared with aberrant DNA methylation. It is quite possible that other histone modifications change coordinately or inversely with DNA methylation, but have not yet been studied in gliomas.