UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth
Menée in vitro et à l'aide de xénogreffes sur un modèle murin, cette étude met en évidence le rôle de l'UDP-glucose pyrophosphorylase 2 (une enzyme régulant la synthèse de glycogène et la glycosylation) dans la croissance d'un cancer du pancréas
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is one of the most deadly cancer types, with a 5-y survival rate below 10%. One reason for this high mortality rate is that PDAC cells have an enhanced ability to survive and proliferate despite existing in nutrient-deprived environments. Understanding the metabolic rewiring that enables nutrient scavenging and rapid metabolic processing of PDAC cells can provide new strategies to develop effective treatment options for this intractable disease. In this study, convergent findings reveal that UGP2 has a central role in the growth and metabolism of PDAC cells through the regulation of glycogen synthesis and protein N-glycosylation, highlighting therapeutic possibilities for this deadly cancer.UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)–TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.All study data reported in this article are included in the main text and/or SI Appendix.