Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis

Abstract

Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.

Keywords: DNA; Krebs cycle; TCA cycle; acetylation; glioblastoma; glioma; gluconeogenesis; glutamine; glycolysis; histones; methylation; microRNAs; oxidative phosphorylation; pentose phosphate pathway.

Figure 1

Crosstalk of epigenetic changes with glycolysis and lipid metabolism in GB. CpG promoter hypomethylation increases CAV-1 expression, stimulating GLUT3 transcription. Moreover, HK2 promoter hypomethylation and PKM hypomethylation promote aerobic glycolysis. Additional glycolytic gene promoters in mesenchymal subtype GBs, including ENO1, GLAM, HK3, GAPDH, and LDHA, are further upregulated by hypomethylation. Elevated histone mark H3K27me3 expression on the EAF2 promoter favor its transcription and a shift towards glycolysis. Histone deacetylation has been involved in the elevation of c-myc expression, which interacts with miR-let-7a, PKM2, and hnRNPA1 to ensure PKM2 upregulation. MiR-let-7a and miR-34c inhibit PKM2 and c-myc signaling. TP53TG1 lncRNA increases GRP78 and IDH1 expression. MiRNAs can downregulate GLUT3 and inhibit glycolysis at various levels (HK1/2/3 and PKM2) as well as the PI3K/Akt pathway. Diffuse midline gliomas with H3K27M mutation, exhibit upregulation of glycolysis and the TCA cycle. In addition, OXPHOS is increased, and lipid metabolism is shifted towards cholesterol synthesis. This is achieved by a network of molecules including EGFR, which upregulates miR-29 that then increases SREBP-1 and SCAP.

Figure 2

Molecular alterations inducing metabolic reprogramming in gliomas. (A) In WT-IDH glioblastoma, α-KG upregulates the action of TET2, which increases the action of DNA demethylases and results in decreased DNA methylation. Conversely, in grade 4 IDH-mutant astrocytomas, mIDH shunts the TCA cycle towards the production of 2-HG instead of α-KG. The decreased levels of α-KG, along with the increased levels of 2-HG, inhibit TET2, which leads to inhibition of DNA demethylases, generating a DNA hypermethylation phenotype. (B) In diffuse midline gliomas, H3K27M mutation inhibits the auto-methylation of EZH2, a PRC2 subunit, leading to decreased H3K27me3 levels. Additionally, in these tumors, the TCA cycle is upregulated to generate α-KG which serves as a co-factor for demethylases leading to further reduction in H3K27me3 levels.

Figure 3

Crosstalk of epigenetic changes and mitochondrial metabolism in GB. High -grade GB mitochondrial DNA is heavily methylated, especially at the POLGA gene, resulting in increased glycolysis instead of OXPHOS to sustain high proliferation rates. Mieap downregulation through promoter methylation further contributes to mitochondrial dysfunction. PDK4 is upregulated through promoter hypomethylation in favor of aerobic glycolysis. Glioma DNA hypermethylation is also associated with IDH1/2 mutations, which generate the 2-HG oncometabolite instead of the α-KG. This decreases the activity of TET2 enzyme and its downstream demethylases, promoting a hypermethylation phenotype. miRNA-153 may act on glutaminases to decrease glutamine metabolism, leading to lactate build up, nucleotide production, and tumor resistance to treatment.