Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions

Abstract

A defining hallmark of glioblastoma is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. Altered metabolic enzymes and their metabolites are oncogenic and not simply a product of tumor proliferation. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field.

Keywords: Warburg effect; epigenetics; metabolic reprogramming; molecular signaling.

Fig. 1.

Nonproliferating versus proliferating metabolism. Normal cells: glucose enters the cell through a glucose transporter and undergoes glycolysis, which generates pyruvate. Pyruvate then enters the mitochondria and undergoes the tricarboxylic acid (TCA) cycle to generate a net of 36 ATP through the process of oxidative phosphorylation. ATP in normal cells is the energy currency of the cell as many biological reactions are coupled to ATP hydrolysis, releasing the free energy to allow for essential reactions to occur. Cancer Cells: cancer cells ferment glucose into lactate, even in the presence of abundant oxygen, and this process is called aerobic glycolysis or the Warburg effect. Although, ATP production is less efficient in aerobic glycolysis compared with complete oxidative metabolism of glucose as in normal cells, tumor cells use aerobic glycolysis to generate precursors for anabolism to grow and generate enough ATP to maintain cell function. By modulating glycolysis and altering mitochondrial metabolism, tumor cells can divert glycolytic/ tricarboxylic acid (TCA) intermediates to generate biomass, namely nucleotides, lipids, proteins, and NADPH to combat oxidative stress. These cells also generate large amounts of lactate for several protumor growth functions, as described in this review.

Fig. 2.

Molecular signaling and the advantages of Warburg. The PI3K-AKT-mTOR signaling pathway, which is highly deregulated in glioblastoma, directly regulates glycolysis and the tricarboxylic acid (TCA) cycle at numerous steps. AKT can promote aerobic glycolysis by promoting increases in glucose transport and hexokinase activity (HK2). Increased AKT activity can also promote ACL-dependent conversion of citrate to cytosolic acetyl-CoA for fatty acid synthesis. Increased glycolysis can promote nucleotide synthesis and generate NADH-reducing equivalents for REDOX. Inactive PKM2 can slow the rate of glycolysis diverting intermediate metabolites to anabolic pathways. mTORC1 stabilization of HIF1a can promote PDK1 activity, diverting pyruvate into lactate generation.

Fig. 3.

Impact of IDH1 and PKM2 on tumor epigenetics. (A) Mutant IDH1 generates 2-hydroxyglutarate (2HG), an oncometabolite that contributes to HIF1a stabilization and a CpG island methylator phenotype (CIMP) through chromatin remodeling and DNA methylation. (B) A novel role for the metabolic enzyme PKM2 in cancer epigenetics. EGFR activation and translocation of PKM2 promote oncogene activation by HDAC dissociation.

Fig. 4.

Tumor microenvironment. Glioblastoma comprises vast cellular and spatial heterogeneity. In addition to bulk tumor, several tumor cell types, including brain tumor-initiating cells and progenitor cells are also present. In addition to tumor cells, glioblastoma tumors also contain nontumor resident microglia and infiltrating immune cells.