Regulation of Glycolysis and the Warburg Effect by Estrogen-related Receptors

Cancer cells typically display altered glucose metabolism characterized by a preference of aerobic glycolysis, known as the Warburg effect, which facilitates cell proliferation. Hypoxia-inducible factor (HIF) and oncoprotein Myc are two prominent transcription factors that drive glycolysis. Previously we reported that the estrogen-related receptors (ERRs) act as cofactors of HIF and enhance HIF-dependent transcription of glycolytic genes under hypoxia. ERRs are orphan nuclear receptors and key regulators of energy metabolism by orchestrating mitochondrial biogenesis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS). Here we show that ERRs also stimulate glycolysis under normoxia. ERRs directly bind to and activate promoters of many genes encoding glycolytic enzymes, and the ERR-binding sites in such promoters are essential for ERR-mediated transcriptional activation. ERRs interact with Myc, and the two factors synergistically activate transcription of glycolytic genes. Furthermore, overexpression of ERRs increases glycolytic gene expression and lactate production. Conversely, depletion of ERRs in cancer cells reduces expression of glycolytic genes and glucose uptake, resulting in decreased aerobic glycolysis and cell growth. Taken together, these results suggest that ERRs are important transcriptional activators of the glycolytic pathway and contribute to the Warburg effect in cancer cells.