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 regulate β-catenin expression via modulation of the O-GlcNAcylation process. TOP/FOP-Flash and real-time qPCR analysis showed that GFAT1 knockdown inhibited β-catenin activity and the transcription of its downstream target genes CCND1 and MYC. Ectopic expression of a stabilized form of β-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 maintaining β-catenin activity in PDAC.
Highlights
Reprogrammed energy metabolism is emerged as a hallmark of cancer cells [1]
As a result, increased hexosamine biosynthesis pathway (HBP) activity was closely associated with an adverse clinical outcome in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), kidney chromophobe (KICH), lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and pancreatic adenocarcinoma (PAAD) (Table 1)
It has been well documented that HBP/O-GlcNAcylation process is critical to tumorigenesis [22]
Summary
Reprogrammed energy metabolism is emerged as a hallmark of cancer cells [1]. Cancer cells are addicted to the amino acid glutamine to fuel anabolic processes [4]. As a branch of glucose and glutamine metabolism, the hexosamine biosynthesis pathway (HBP) consumes approximately 2-5% of the total glucose and a small fraction of glutamine to generate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) [5]. UDP-GlcNAc is profoundly implicated in the classical glycosylation and OGlcNAcylation process, which posttranslationally modifies many cytosolic and nuclear proteins by O-linked-N-acetylglucosamine (O-GlcNAc) [6]. O-GlcNAcylation has been reported to link the HBP to malignant activities, its activity and prognostic value in human cancers remain largely unexplored [7,8,9]
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