Endocrine Abstracts

The nutrient demands of cancer cannot be met by normal cell metabolism. Cancer cells undergo dramatic alteration of metabolic pathways in a process called reprogramming, characterized by increased nutrient uptake and re-purposing of these fuels for biosynthetic, bioenergetic or signaling pathways. Partitioning carbon sources toward growth and away from ATP production necessitates other means of generating energy for biosynthetic reactions. While much research has examined the use of glucose and glutamine by tumor cells, a subset of cancers have a high capacity and preference for fat oxidation. Our knowledge of pathways that drive dependency on fatty acid oxidation in cancer is limited. Prolyl hydroxylase domain proteins (PHDs, also called EGLN1–3) are a family of oxygen and α-ketoglutarate dependent enzymes that have been linked to fuel switching in cancer. Through their unique ability to integrate cellular stress and nutrient status with coordination of metabolic outputs, PHDs are well poised to play pivotal roles in tumor progression and survival. PHDs are well known to regulate glycolytic metabolism through prolyl hydroxylation of the master transcriptional regulator hypoxia-inducible factor. Here, we reveal a novel mechanism through which the PHD family of proteins regulates the use of an alternative fuel in cancer: fatty acids. We find that PHD status serves as an indicator of fatty acid metabolic status and informs the susceptibility of a particular cancer to pharmacological inhibitors of fatty acid oxidation.