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.
Highlights
Genetic information and the pattern in which genes are expressed are both important for properties of cells
We provide an overview of epigenetic regulation and possible therapeutic interventions of alternative lengthening of telomeres (ALT) identified in normal and cancer cells with a focus on diffuse gliomas as one special group of tumors located in the brain with diverse patient outcome depending on telomere maintenance mechanisms (TMMs) used
Recent studies support the notion that neural stem cell (NSC), astrocyte and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin with implication in the development of effective therapeutic treatment methods [90]
Summary
Genetic information and the pattern in which genes are expressed are both important for properties of cells. Gene expression patterns important for cell phenotype and function need to be both adaptable and heritable. Adaptable gene expression patterns are often responses to stimulation and based on non-genetic determinants that are summarized as epigenetic mechanisms (EMs) with fundamental implications for cancer especially in combination with heritable mutations [1,2]. These EMs currently include covalent modification of DNA, covalent modification of histones, non-protein-coding RNAs (ncRNAs) such as short microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). We provide an overview of epigenetic regulation and possible therapeutic interventions of ALT identified in normal and cancer cells with a focus on diffuse gliomas as one special group of tumors located in the brain with diverse patient outcome depending on TMM used
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