Integrated Transcriptomic and Proteomic Analyses Reveal Role of the Hexosamine Biosynthetic Pathway in Invasion and Metastasis of Hepatocellular Carcinoma

It was recently found that the effect of an exercise-induced increase in muscle GLUT-4 on insulin-stimulated glucose transport is masked by a decreased responsiveness to insulin in glycogen-supercompensated muscle. We evaluated the role of hexosamines in this decrease in insulin responsiveness and found that UDP- N-acetyl hexosamine concentrations were not higher in glycogen-supercompensated muscles than in control muscles with a low glycogen content. We determined whether the smaller increase in glucose transport is due to translocation of fewer GLUT-4 to the cell surface with the 2- N-4-(1-azi-2,2,2-trifluroethyl)-benzoyl-1,3-bis(d-mannose-4-yloxy)-2-propylamine (ATB-[2-3H]BMPA) photolabeling technique. The insulin-induced increase in GLUT-4 at the cell surface was no greater in glycogen-supercompensated exercised muscle than in muscles of sedentary controls and only 50% as great as in exercised muscles with a low glycogen content. We conclude that the decreased insulin responsiveness of glucose transport in glycogen-supercompensated muscle is not due to increased accumulation of hexosamine biosynthetic pathway end products and that the smaller increase in glucose transport is mediated by translocation of fewer GLUT-4 to the cell surface.

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Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway

Circulation Research ◽

10.1161/res.115.suppl_1.261 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Zhao V Wang ◽

Yingfeng Deng ◽

Ningguo Gao ◽

Zully Pedrozo ◽

Dan Li ◽

...

Keyword(s):

Unfolded Protein Response ◽

Biosynthetic Pathway ◽

Ischemia Reperfusion ◽

Uridine Diphosphate ◽

Hexosamine Biosynthetic Pathway ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Rate Limiting

Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined. Methods & Results: Here, we show that spliced Xbp1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation. Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.

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Regulatory role of hexosamine biosynthetic pathway on hepatic cancer stem cell marker CD133 under low glucose conditions

Scientific Reports ◽

10.1038/srep21184 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 10

Author(s):

Shu-Hai Lin ◽

Tengfei Liu ◽

Xiaoyan Ming ◽

Zhi Tang ◽

Li Fu ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Biosynthetic Pathway ◽

Stem Cell Marker ◽

Hepatic Cancer ◽

Cancer Stem Cell Marker ◽

Cell Marker ◽

Hexosamine Biosynthetic Pathway ◽

Low Glucose

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Role of Hexosamine Biosynthetic Pathway on Cancer Stem Cells: Connecting Nutrient Sensing to Cancer Cell Plasticity

Reference Module in Biomedical Sciences ◽

10.1016/b978-0-12-820472-6.00038-4 ◽

2021 ◽

Author(s):

Giang Le Minh ◽

Mauricio J. Reginato

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cell ◽

Biosynthetic Pathway ◽

Nutrient Sensing ◽

Cell Plasticity ◽

Hexosamine Biosynthetic Pathway

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Role of MicroRNAs Induced by Chinese Herbal Medicines Against Hepatocellular Carcinoma: A Brief Review

Integrative Cancer Therapies ◽

10.1177/1534735418805564 ◽

2018 ◽

Vol 17 (4) ◽

pp. 1059-1067 ◽

Cited By ~ 1

Author(s):

Ge Guo ◽

Juhua Zhou ◽

Xiaogaung Yang ◽

Jiang Feng ◽

Yanxia Shao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Small Rnas ◽

Herbal Medicines ◽

Early Embryo ◽

Invasion And Metastasis ◽

Chinese Herbal Medicines ◽

Regulate Gene Expression ◽

Early Embryo Development ◽

Chinese Herbal

MicroRNAs (miRNAs) are highly conserved, noncoding small RNAs that regulate gene expression, and consequently several important functions including early embryo development, cell cycle, programmed cell death, cell differentiation, and metabolism. While there are no effective treatments available against hepatocellular carcinoma (HCC), some Chinese herbal medicines have been shown to regulate growth, differentiation, invasion, and metastasis of HCC. Many studies have shown that Chinese herbal medicines regulate the expression of miRNAs and this may be associated with their ability to control the development of HCC. In this article, the effects of Chinese herbal medicines on the expression of miRNAs and their functions in the regulation of HCC have been reviewed and discussed. miRNAs such as miRNA-221 and miRNA-222 mediated by Chinese herbal medicines may be good biomarkers and therapeutic targets for HCC.

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Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression

PeerJ ◽

10.7717/peerj.2348 ◽

2016 ◽

Vol 4 ◽

pp. e2348 ◽

Cited By ~ 11

Author(s):

Muhammad Tariq Saeed ◽

Jamil Ahmad ◽

Shahzina Kanwal ◽

Andreana N. Holowatyj ◽

Iftikhar A. Sheikh ◽

...

Keyword(s):

Cancer Progression ◽

Biosynthetic Pathway ◽

Genetic Alterations ◽

Glycolytic Flux ◽

Model Parameters ◽

Modeling Framework ◽

Hexosamine Biosynthetic Pathway ◽

Degradation Rates ◽

Acetylglucosamine Transferase

The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP) drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation) and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT), an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer.

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