UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.

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.
Competing Interests: Competing interest statement: A.L.W. has received research funding from Oncogenuity. M.S. has received research funds from Puma Biotechnology, AstraZeneca, Daiichi-Sankyo, Immunomedics, Targimmune, and Menarini Ricerche. He is on the scientific advisory board of Menarini Ricerche and the Bioscience Institute, a cofounder of medendi.org, and an employee and stockholder of AstraZeneca. F.M. is a consultant for Daiichi-Sankyo, Pfizer, Amgen, BridgeBio, Olema, OPNA-IO, PMV, Quanta, and Remedy Plan and has received research funding from Daiichi-Sankyo.
(Copyright © 2021 the Author(s). Published by PNAS.)