Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) promotes the EMT of serous ovarian cancer by activating the hexosamine biosynthetic pathway to increase the nuclear location of β-catenin

Zhou, Lin; Luo, Mu; Cheng, Lijuan; Li, Ruonan; Liu, Bin; Linghu, Hua

doi:10.1016/j.prp.2019.152681

Cited by 28 publications

(14 citation statements)

References 30 publications

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“…These analyses suggest that GFPT2 is a tumor promoter in claudin-low breast cancer. The role of GFPT2 in mediating glycan synthesis has been reported in a series of studies that show that GFPT2 mediates response via glycosylation of master regulators of metabolism, including NF-κB and β-catenin (21,22). The function of GFPT2 in glutaminolysis is less explored, although its importance has been inferred from its enzymatic activity.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

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Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Wang

Karvelsson

Kotronoulas

et al. 2022

Molecular & Cellular Proteomics

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“…Several studies have focused on the function and regulation of GFPT2 related to its role in modulating O-GlcNAcylation of proteins on account of GFPT2 in producing UDP-GlcNAc (21,22,53). GFPT2 has also been shown to counteract oxidative stress (51,69,70), although the mechanism behind that remains elusive.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Wang

Karvelsson

Kotronoulas

et al. 2022

Molecular & Cellular Proteomics

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“…The data showed that GFPT2 had a positive association with the clinical stage, which was overexpressed in OC tissues. The down-regulated expression of GFPT2 in OC cells could reduce β-catenin nuclear location and the expression level of Slug and Zeb1 ( Zhou et al, 2019 ). Our data also suggest the GFPT2 was a high-risk gene in OC and is related to poor prognosis in OC.…”

Section: Discussionmentioning

confidence: 99%

Predicting Panel of Metabolism and Immune-Related Genes for the Prognosis of Human Ovarian Cancer

Zhang

Sun

Ren

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveOvarian cancer (OC) is a high deadly gynecologic cancer with a poor prognosis. The identification of genomic aberrations could predict the clinical prognosis of OC patients and may eventually develop new therapeutic strategies in the future. The purpose of this study is to create comprehensive co-expressed gene networks correlated with metabolism and the immune process of OC.MethodsThe transcriptome profiles of TCGA OC datasets and GSE26193 datasets were analyzed. The mRNA expression level, hub genomic alteration, patient’s survival status, and tumor cell immune microenvironment of metabolism-related genes were analyzed from TCGA, GTEX, Oncomine, Kaplan-Meier Plotter, cBioPortal, TIMER, ESTIMATE, and CIBERSORT databases. We further validated the mRNA and protein expression levels of these hub genes in OC cell lines and tissues using qRT-PCR and immunohistochemistry.ResultsThe LASSO-Cox regression analyses unveiled seven differently expressed metabolism-related genes, including GFPT2, DGKD, ACACB, ACSM3, IDO1, TPMT, and PGP. The Cox regression risk model could be served as an independent marker to predict the overall clinical survival of OC patients. The expression of GFPT2, DGKD, ACACB, and ACSM3 were downregulated in OC tissues, while IDO1, TPMT, and PGP were upregulated in OC tissues than in control. Moreover, DGKD and IDO1 were significantly associated with the human immune system.ConclusionThe differently expressed metabolism-related genes were identified to be a risk model in the prediction of the prognosis of OC. The identified hub genes related to OC prognosis may play important roles in influencing both human metabolism and the immune system.

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“…For example, increased glucose levels are correlated with endometrial cancer through upregulation of the HBP and O-GlcNAcylation, which enhances the stability of β-catenin [31]. Many reports have also revealed that the increased O-GlcNAcylation level is able to increase the β-catenin activity, nuclear accumulation, and subsequent transcription of its target genes [31,[34][35][36]. In colorectal cancer, upregulation of the HBP reverberates on high O-GlcNAcylation levels including modification of β-catenin to promote cell proliferation [37].…”

Section: Discussionmentioning

confidence: 99%

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

Jia

et al. 2020

BioMed Research International

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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-lnorleucine (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.

show abstract

Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) promotes the EMT of serous ovarian cancer by activating the hexosamine biosynthetic pathway to increase the nuclear location of β-catenin

Cited by 28 publications

References 30 publications

Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Predicting Panel of Metabolism and Immune-Related Genes for the Prognosis of Human Ovarian Cancer

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

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