An interesting study unraveled a novel signaling axis that regulates cancer metabolism through the non-proteolytic ubiquitylation of hexokinase 2 (HK2), a critical enzyme upstream of many glycolytic pathways, by the HECT-type E3 ligase HECTH9 (or HUWE1)138 (Fig. 5a). This evidence concerns the gene HUWE1 and cancer.