Affiliation:
1. Department of Gastroenterology, Beijing Jishuitan Hospital, Beijing 100035, China
2. Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
Abstract
Reprogrammed glucose and glutamine metabolism are essential for tumor initiation and development. As a branch of glucose and metabolism, the hexosamine biosynthesis pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and contributes to the O-GlcNAcylation process. However, the spectrum of HBP-dependent tumors and the mechanisms by which the HBP promotes tumor aggressiveness remain areas of active investigation. In this study, we analyzed the activity of the HBP and its prognostic value across 33 types of human cancers. Increased HBP activity was observed in pancreatic ductal adenocarcinoma (PDAC), and higher HBP activity predicted a poor prognosis in PDAC patients. Genetic silencing or pharmacological inhibition of the first and rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), inhibited PDAC cell proliferation, invasive capacity, and triggered cell apoptosis. Notably, these effects can be restored by addition of UDP-GlcNAc. Moreover, similar antitumor effects were noticed by pharmacological inhibition of GFAT1 with 6-diazo-5-oxo-l-norleucine (DON) or Azaserine. PDAC is maintained by oncogenic Wnt/β-catenin transcriptional activity. Our data showed that GFAT1 can regulateβ-catenin expression via modulation of the O-GlcNAcylation process. TOP/FOP-Flash and real-time qPCR analysis showed that GFAT1 knockdown inhibitedβ-catenin activity and the transcription of its downstream target genesCCND1andMYC. Ectopic expression of a stabilized form ofβ-catenin restored the suppressive roles of GFAT1 knockdown on PDAC cell proliferation and invasion. Collectively, our findings indicate that higher GFAT1/HBP/O-GlcNAcylation exhibits tumor-promoting roles by maintainingβ-catenin activity in PDAC.
Funder
Chinesisch-Deutsche Kooperationsgruppe: Precision Medicine in Pancreatic Cancer
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine
Cited by
24 articles.
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