GFAT1 promotes the progression of hepatocellular carcinoma via enhancing the O-GlcNAcylation of VEZF1 [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1166669 | ENA |
REPOSITORIES: ENA
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Project description:Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the first rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), is a key factor controlling HBP flux. However, the molecular mechanism underlying the roles of GFAT1 in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we found that GFAT1 was upregulated in HCC, and high GFAT1 level was correlated with poor patient prognosis. Our in vitro and in vivo studies demonstrated that GFAT1 facilitated hepatoma cell proliferation and invasion by enhancing HBP and O-GlcNAcylation through its enzymatic activity. Global profiling of O-GlcNAcylation identified vascular endothelial zinc finger protein 1 (VEZF1) as a substrate heavily O-GlcNAcylated in GFAT1-overexpressing hepatoma cells. Notably, O-GlcNAcylation at specific serine residues (Ser123 and Ser124) within VEZF1 attenuated its proteasomal degradation, thereby enhancing its protein stability and promoting tensin 1 (TNS1) transcription in HCC. In addition, we designed a bioactive VEZF1-derived peptide to competitively inhibit GFAT1-mediated O-GlcNAcylation of VEZF1. This intervention effectively reduced TNS1 expression and suppressed the progression of HCC in a mouse model. Together, these findings highlight the therapeutic potential of targeting the GFAT1-VEZF1-TNS1 signaling axis in HCC.
2025-08-26 | GSE278232 | GEO
Project description:Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the first rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), is a key factor controlling HBP flux. However, the molecular mechanism underlying the roles of GFAT1 in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we found that GFAT1 was upregulated in HCC, and high GFAT1 level was correlated with poor patient prognosis. Our in vitro and in vivo studies demonstrated that GFAT1 facilitated hepatoma cell proliferation and invasion by enhancing HBP and O-GlcNAcylation through its enzymatic activity. Global profiling of O-GlcNAcylation identified vascular endothelial zinc finger protein 1 (VEZF1) as a substrate heavily O-GlcNAcylated in GFAT1-overexpressing hepatoma cells. Notably, O-GlcNAcylation at specific serine residues (Ser123 and Ser124) within VEZF1 attenuated its proteasomal degradation, thereby enhancing its protein stability and promoting tensin 1 (TNS1) transcription in HCC. In addition, we designed a bioactive VEZF1-derived peptide to competitively inhibit GFAT1-mediated O-GlcNAcylation of VEZF1. This intervention effectively reduced TNS1 expression and suppressed the progression of HCC in a mouse model. Together, these findings highlight the therapeutic potential of targeting the GFAT1-VEZF1-TNS1 signaling axis in HCC.
2025-08-26 | GSE278334 | GEO
Project description:GFAT1 promotes the progression of hepatocellular carcinoma via enhancing the O-GlcNAcylation of VEZF1
| PRJNA1166144 | ENA
Project description:The protein Vezf1 plays multiple roles important for embryonic development. In Vezf1-/- mouse embryonic stem (MES) cells our earlier data showed widespread changes in gene expression profiles, including decreased expression of the full length active isoform of Dnmt3b methyltransferase and concomitant genome wide reduction in DNA methylation. Here we show that, in HeLaS3 cells, there is a strong genome-wide correlation between Vezf1 binding and peaks of elongating Ser2-P Pol ll, reflecting Vezf1 dependent slowing of elongation. In Wt MES cells the elongating form of RNA polymerase II accumulates near Vezf1 binding sites within the dnmt3b gene and at several other Vezf1 sites, and this accumulation is significantly reduced at these sites in Vezf1-/- MES cells. Depending upon genomic location, Vezf1 mediated Pol II pausing can have different regulatory roles in transcription and splicing. We find examples of genes in which Vezf1 binding sites are located near cassette exons, and in which loss of Vezf1 leads to a change in the relative abundance of alternatively spliced messages. We further show that Vezf1 interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 tri-methylation, consistent with the role of histone modifications at alternatively spliced sites.
2012-03-09 | GSE34785 | GEO
Project description:The protein Vezf1 plays multiple roles important for embryonic development. In Vezf1-/- mouse embryonic stem (MES) cells our earlier data showed widespread changes in gene expression profiles, including decreased expression of the full length active isoform of Dnmt3b methyltransferase and concomitant genome wide reduction in DNA methylation. Here we show that, in HeLaS3 cells, there is a strong genome-wide correlation between Vezf1 binding and peaks of elongating Ser2-P Pol ll, reflecting Vezf1 dependent slowing of elongation. In Wt MES cells the elongating form of RNA polymerase II accumulates near Vezf1 binding sites within the dnmt3b gene and at several other Vezf1 sites, and this accumulation is significantly reduced at these sites in Vezf1-/- MES cells. Depending upon genomic location, Vezf1 mediated Pol II pausing can have different regulatory roles in transcription and splicing. We find examples of genes in which Vezf1 binding sites are located near cassette exons, and in which loss of Vezf1 leads to a change in the relative abundance of alternatively spliced messages. We further show that Vezf1 interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 tri-methylation, consistent with the role of histone modifications at alternatively spliced sites. Comparison of Vezf1 and RNA Pol II binding in mouse and human cells.
2012-03-09 | E-GEOD-34785 | biostudies-arrayexpress
Project description:The RNA M5C Methyltransferase NSUN2 Promotes Progression of Hepatocellular Carcinoma by Enhancing PKM2-Mediated Glycolysis
| PRJNA1168600 | ENA
Project description:In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC.
2024-01-04 | PXD048234 |
Project description:This SuperSeries is composed of the following subset Series: GSE33049: GlcNAcylation of histone H2B facilitates its monoubiquitination [Illumina Genome Analyzer data] GSE33050: GlcNAcylation of histone H2B facilitates its monoubiquitination [Affymetrix data] Refer to individual Series
2011-10-26 | E-GEOD-33051 | biostudies-arrayexpress
Project description:Reactive oxygen species (ROS) play a crucial role in lipid peroxidation and the initiation of ferroptosis, significantly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, as a sensor for ROS induced by ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT O-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2's nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting ferroptosis. The elevated OGT-FOXK2-SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-O-GlcNAcylation cascade that integrates ROS signaling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription, and resistance to both ferroptosis and chemoradiotherapy.
2025-05-28 | PXD064117 | Pride
Project description:We performed a set of sequencing experiments to identify the targets of Vascular endothelial zinc finger 1 (Vezf1) in neonatal rat cardiomyocytes. We compared a set of control samples to samples transfected with Vezf1 siRNA by high throughput sequencing. Vascular endothelial zinc finger 1 (Vezf1) siRNA was transfected into the neonatal rat ventricular cardiomyocytes for 24h and thereafter the cells were incubated in serum free medium for 48h.
2019-11-30 | E-MTAB-7124 | biostudies-arrayexpress