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.

Telomere Maintenance Mechanisms in Cancer

“…TERT regulation by miRNA was summarized by Lewis et al [ 420 ]. It was proposed that miRNAs can post-transcriptionally alter TERT transcripts directly or indirectly, affecting regulatory transcription factors [ 5 , 420 ]. TERRA transcripts are other types of non-coding RNAs found in eukaryotes that will be further addressed due to their association in ALT.…”

“…ATRX / DAXX mutations are thus suggested to be strong contributors to the activation of the ALT pathway. New evidence of epigenetic mechanisms affecting ALT were recently reported, such as microRNA regulation, as reviewed by Naderlinger et al [ 5 ]. This mechanism has also been reported to correlate with high levels of TERRA [ 456 ].…”

“…Telomeres are DNA–protein complexes at the ends of eukaryotic chromosomes that play a crucial role in cellular survival, by limiting progressive loss of genomic information caused by semi-conservative replication of DNA [ 1 , 2 ]. Most cancer cells maintain the integrity of their telomeres by telomerase reactivation (TR) [ 3 ], and the mechanisms accounting for telomere length (TL) maintenance are currently known to comprise transcriptional, post-transcriptional, and epigenetic regulation [ 4 , 5 ]. A small part of tumour cells acquires immortality through the alternative lengthening of telomeres (ALT) mechanism.…”

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

“…Pieces of evidence have shown that the ALT mechanism is particularly responsive to telomeric epigenetic modifications [49]. Methionine restriction, which affects DNA methyltransferase (DNMT) activity, results in a rapid accumulation of APBs [50], whereas depletion of anti-silencing function 1a/1b histone chaperones, which coordinate the shuttling of histone proteins during DNA replication, or of histone deacetylase 5 (HDAC5), results in ALT induction (i.e., APB formation or telomere recombination) in telomerase-positive cancer cell lines [51,52].…”

The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor

“…Some reviews have already pointed out emerging targets for GBM therapy [ 128 , 129 , 130 , 131 ]. Here, we investigated the main studies focusing on Wnt pathways, which has been positively correlated to the genesis and progression of GBMs, as confirmed by the altered expression of different members of Wnt associated with a bad prognosis in GBM patients.…”