FIGURE 4.

The positive feedback loop of metabolism–epigenetics–gene regulation. As delineated throughout this review, a positive feedback loop underpins the progression of malignant growth. Nuclear metabolites, which may be derived from extracellular sources, along with intranuclear metabolic enzymes, serve as cosubstrates, cofactors, or regulators in instigating epigenetic changes. These changes either promote or inhibit the expression of a myriad of genes, subsequently amplifying metabolic activity within the cell. Metabolism, in turn, exerts a direct influence on gene functionality via posttranslational modifications, protein processing, and nuclear translocation, among other mechanisms. Research exploring the direct ramifications of epigenetic changes on metabolic activity—specifically, how chromatin modifications may influence cellular metabolism via nongenomic routes—is relatively scant, underscoring the complexity of the interactions shaping malignant tumorigenesis.