Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer

Simple Summary Cancer cells change their metabolism to support a chaotic and uncontrolled growth. In addition to meeting the metabolic needs of the cell, these changes in metabolism also affect the patterns of gene activation, changing the identity of cancer cells. As a consequence, cancer cells become more aggressive and more resistant to treatments. In this article, we present a review of the literature on the interactions between metabolism and cell identity, and we explore the mechanisms by which metabolic changes affect gene regulation. This is important because recent therapies under active investigation target both metabolism and gene regulation. The interactions of these new therapies with existing chemotherapies are not known and need to be investigated. Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.