GFAT1/HBP/O-GlcNAcylation Axis Regulates β -Catenin Activity to Promote Pancreatic Cancer Aggressiveness

BioMed Research International
Chunzeng JiaYu Lan

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 ca...Continue Reading

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Citations

Nov 17, 2020·Frontiers in Oncology·Donglu WuHaoming Luo
Mar 18, 2021·European Biophysics Journal : EBJ·Anna SobiepanekTomasz Kobiela

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Methods Mentioned

BETA
glycosylation
Protein Assay
immunoprecipitation
Assay
acetylation

Software Mentioned

ImageJ Image
GraphPad Prism
SPSS

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