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.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2021 Aug 3|
Bibliographical noteFunding Information:
Author contributions: A.L.W., Q.Z., E.T., M.S., C.B.L., F.M., and S.E.K. designed research; A.L.W., Q.Z., E.T., J.G., and S.E.K. performed research; A.L.W., Q.Z., E.T., A.A.K., R.P.K., S.B., F.M., and S.E.K. analyzed data; and A.L.W., Q.Z., F.M., and S.E.K. wrote the paper. Reviewers: A.L.H., University of Oxford; and A.K., New York University Langone Medical Center. 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.
ACKNOWLEDGMENTS. We thank the UCSF Biorepository & Tissue Biomarker Technology Core for tissue microarray image analysis. HistoWiz, Inc. performed immunohistochemical staining of murine tumors, and UDP-glucose levels were measured by Metabolon, Inc. Patient PDAC mRNA expression data were generated by The Cancer Genome Atlas Research Network. We thank members of the F.M. laboratory for discussions and critical reading of the manuscript. A.L.W. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation through postdoctoral fellowship number DRG-2214-15. Research reported in this publication was supported by the National Cancer Institute of the NIH under Award K99CA226363 (to A.L.W.). Funding for this work was provided by NIH Grant R01GM049077 (to Q.Z. and C.B.L.), Memorial Sloan Kettering Cancer Center Support Grant/ Core Grant P30 CA008748 (to M.S.), and UCSF Research Allocation Program and National Research Foundation of Korea Grant NRF-2020R1C1C1013220 (to S.E.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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