Phosphomevalonate Kinase Controls β‐Catenin Signaling via the Metabolite 5‐Diphosphomevalonate

β-catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize β-catenin signaling using a human genome-wide library. On the one hand, PMVK-produced MVA-5PP competitively binds to CKIα to prevent β-catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate β-catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA-5PP together promotes β-catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl4 -induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non-canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and β-catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.