Journal Article

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

Bandyopadhyay, Sourav, Koche, Richard P., Wolfe, Andrew L., Zhou, Qingwen, Galeas, Jacqueline, Ku, Angel A., McCormick, Frank, Kim, Sung Eun, Toska, Eneda, Scaltriti, Maurizio, Lebrilla, Carlito B.

2021

Overview

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.

• Publisher: National Academy of Sciences,Proceedings of the National Academy of Sciences
• Subject: 2.1 Biological and endogenous factors / Adenocarcinoma / Aetiology / Animals / Biological Sciences / Cancer / Carcinoma / Carcinoma, Pancreatic Ductal / Carcinoma, Pancreatic Ductal - enzymology / Carcinoma, Pancreatic Ductal - pathology / Cell Line / Cell Line, Tumor / Digestive Diseases / Enzymologic / Epidermal growth factor / Experimental / Gene Expression Regulation / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Enzymologic - physiology / Gene Expression Regulation, Neoplastic / Gene Expression Regulation, Neoplastic - physiology / Gene Knockdown Techniques / Glucose / Glycogen / Glycogen - biosynthesis / Glycogens / Glycosylation / Growth factors / Humans / Maintenance / Medical Sciences / Metabolic pathways / Metabolism / Mice / Mice, Nude / N-glycosylation / Neoplasms / Neoplasms, Experimental / Neoplastic / Nude / Pancreatic Cancer / Pancreatic Ductal / Pancreatic Neoplasms / Pancreatic Neoplasms - enzymology / Pancreatic Neoplasms - pathology / PDAC / Protein turnover / Proteins / Rare Diseases / TEA Domain Transcription Factors / TEA Domain Transcription Factors - genetics / TEA Domain Transcription Factors - metabolism / Tumor / Tumors / UDP-glucose / UGP2 / Uridine / UTP-Glucose-1-Phosphate Uridylyltransferase / UTP-Glucose-1-Phosphate Uridylyltransferase - genetics / UTP-Glucose-1-Phosphate Uridylyltransferase - metabolism / YAP-Signaling Proteins / YAP-Signaling Proteins - genetics / YAP-Signaling Proteins - metabolism / Yes-associated protein