Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas

Abstract

High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas. Furthermore, we present new evidence for epigenetic mechanisms (EMs) involved in regulation of ALT and TA with special emphasis on human diffuse gliomas as potential therapeutic drug targets. We discuss the role of TMM associated telomeric chromatin factors such as DNA and histone modifying enzymes and non-coding RNAs including microRNAs and long telomeric TERRA transcripts.

Keywords: CpG DNA methylation; chromatin modification; epigenetic therapy; high grade glioma; histone deacetylase; histone methylation and acetylation; miRNA; telomere maintenance; telomeric repeat-containing RNA.

Figure 1

Schematic overview of EMs regulating ALT and their potential interplay. ALT activity is regulated via a complex network of epigenetic modifiers. The effects are marked with arrows or inhibitory arrows in black. EM marked by colors: DNA (green), RNA (blue) and histone (red). In addition to influencing ALT activity they also interact with each other (grey dotted lines).

Figure 2

Schematic examples of potential epigenetic therapy targeting ALT and TA in glioma. Left: Inhibitory compounds against histone deacetylase HDAC class I and IIa may affect directly both ALT and TA. Right: The histone chaperones ATRX/DAXX deposit the H3.3 at telomeric chromatin and thereby maintain silencing histone marks such as H3K9me3 and H3K27me3. Demethylase inhibitors block demethylation of H3 with possible change in chromatin structure that may block directly ALT and TA via LINE-1. Symbols as defined in Figure 1.