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

Abstract

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.

• Authors: Andrew L Wolfe, Qingwen Zhou, Eneda Toska, Jacqueline Galeas, Angel A Ku, Richard P Koche, Sourav Bandyopadhyay, Maurizio Scaltriti, Carlito B Lebrilla, Frank McCormick, Sung Eun Kim
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 31 (08 03 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34330832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• TEA Domain Transcription Factors
• TEAD1 protein, human
• YAP-Signaling Proteins
• YAP1 protein, human
• Glycogen
• UTP-Glucose-1-Phosphate Uridylyltransferase

Topics

• Animals
• Carcinoma, Pancreatic Ductal (enzymology, pathology)
• Cell Line, Tumor
• Gene Expression Regulation, Enzymologic (physiology)
• Gene Expression Regulation, Neoplastic (physiology)
• Gene Knockdown Techniques
• Glycogen (biosynthesis)
• Glycosylation
• Humans
• Mice
• Mice, Nude
• Neoplasms, Experimental
• Pancreatic Neoplasms (enzymology, pathology)
• TEA Domain Transcription Factors (genetics, metabolism)
• UTP-Glucose-1-Phosphate Uridylyltransferase (genetics, metabolism)
• YAP-Signaling Proteins (genetics, metabolism)