Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 31, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2103592118
Keywords
PDAC; UGP2; UDP-glucose; glycogen; N-glycosylation
Categories
Funding
- Damon Runyon Cancer Research Foundation [DRG-2214-15]
- National Cancer Institute of the NIH [K99CA226363]
- NIH [R01GM049077]
- Memorial Sloan Kettering Cancer Center Support Grant/Core Grant [P30 CA008748]
- UCSF Research Allocation Program
- National Research Foundation of Korea [NRF-2020R1C1C1013220]
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The enzyme UGP2, which synthesizes UDP-glucose, plays a crucial role in maintaining pancreatic ductal adenocarcinoma (PDAC) growth. Its transcription is directly regulated by the YAP-TEAD complex, and loss of UGP2 leads to decreased glycogen levels and defects in glycosylation of important targets for PDAC survival.
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.
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