Epigenetic dysregulation in glioma

Abstract

Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

Fig. 1

Genetic and epigenetic alterations in gliomas. TP53, IDH1 and ATRX are frequently mutated in low-grade gliomas and secondary GBM. Mutation of IDH1 leads to aberrant DNA methylation, whereas mutations in the important chromatin modifier ATRX affect chromatin structure. In pediatric GBM, mutations in H3F3A and ATRX are found frequently and associated closely with gliomagenesis.

Fig. 2

IDH mutations induce G-CIMP. Mutations in IDH1 (a cytoplasmic enzyme) and IDH2 (a mitochondrial enzyme) are found frequently in proneural glioblastoma multiforme (GBM). IDH1 mutations are more common than IDH2 mutations. Mutated IDH1 and IDH2 gain the ability to produce the metabolite, 2-hydroxyglutarate (2-HG), which inhibits α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases and the TET protein family. Therefore, mutation of IDH1 is the mechanistic cause of G-CIMP through inhibition of the TET-mediated production of 5hmC, which is a primary mode of DNA demethylation.

Fig. 3

Roles of PRC in the formation of heterogeneous tumors. (a) Glioma stem cells (GSC) are considered able to differentiate aberrantly into diverse cell types. The process of differentiation of GSC into non-GSC is reversible and shows phenotypic equilibrium. (b) PRC2 has a histone methyltransferase activity with substrate specificity for H3K27 and produces H3K27me3, which is thought to recruit PRC1 via proteins of the CBX family. The RING1A/1B complex in PRC1 induces the mono-ubiquitination of histone 2A lysine 119 (H2AK119), which is thought to affect chromatin structure and block the recruitment of transcriptional activation factors (bottom panel). We have demonstrated that PRC2 is required for the self-renewal of GSCs as well as GSC differentiation in response to oncogenic cues, which leads to the establishment of heterogenous tumors.

Fig. 4

miRNA associated with the maintenance of glioma stem cells (GSC). miR-9/9*, the miR17-92 cluster, and miR-1275 are upregulated in GSC. Targets of these miRNA, namely calmodulin-binding transcription activator 1 (CAMTA1), connective tissue growth factor (CTGF) and CLDN11, act as tumor suppressors. In contrast, miR-34a, miR-128, miR-124 and miR-137 are downregulated in GSC. miR-34a inhibits the expression of Notch1 and Notch2, which are receptors of notch signaling molecules. miR-128 inhibits GSC self-renewal by directly targeting BMI1 and SUZ12, components of PRC1 and PRC2, respectively. miR-124 and miR-137 induce G0/G1 cell cycle arrest by targeting cyclin-dependent kinase 6 (CDK6).