JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

Cancer cells favor high rates of aerobic glycolysis, or the Warburg effect, which is mediated by a key molecule, pyruvate kinase muscle isozyme (PKM)2. PKM2 functions both as a cytosolic enzyme and a nuclear factor in tumor cells. This report shows that PKM2’s nuclear translocation is regulated by Jumonji C domain-containing dioxygenase (JMJD)5 via direct physical binding. JMJD5 hinders the PKM2 tetrameric assembly and facilitates PKM2’s nuclear translocation. Together, they modulate hypoxia-inducible factor 1α-mediated transcriptional reprogramming of metabolic genes. These results reveal a mechanism whereby PKM2’s activity can be modulated by a dioxygenase/demethylase.