Research progress on the role of hexosamine biosynthesis pathway and O-glycosylation inmetabolism of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XU Junhui ,  WANG Weixing

Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;

Corresponding author：

WANG Weixing, Email: sate.llite@163.com

Keywords：

hepatocellular carcinoma; hexosamine biosynthesis pathway; O-glycosylation; metabolish

DOI：

10.7507/1007-9424.202007019

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the characteristics of hexosamine biosynthesis pathway (HBP) and O-glycosylation and their roles in metabolism of hepatocellular carcinoma. Method To review the current literatures on the role of HBP and O-glycosylation in tumors, especially in hepatocellular carcinoma. Results There was metabolic reprogramming in hepatocellular carcinoma cells, and the HBP was a branch of glycolysis pathway, which played an important role in tumorigenesis, development, and metastasis. HBP provided uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) for O-glycosylation, UDP-GlcNAc was a substrate for OGT, participating in O-glycosylation. O-glycosylation was a type of posttranslational modification that regulates the biological behavior of tumor cells by glycosylation of target proteins in tumor cells. Conclusion HBP and O-glycosylation can be used as intervention targets in the treatment of hepatocellular carcinoma, which provides a potential method for scientific prevention and treatment of hepatocellular carcinoma.

Citation： XU Junhui, WANG Weixing. Research progress on the role of hexosamine biosynthesis pathway and O-glycosylation inmetabolism of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(5): 683-687. doi: 10.7507/1007-9424.202007019 Copy

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2.	Ding X, He M, Chan AWH, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology, 2019, 157(6): 1630-1645.
3.	Wang C, Tong Y, Wen Y, et al. Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth. Hepatology, 2018, 68(5): 1833-1850.
4.	DeWaal D, Nogueira V, Terry AR, et al. Author correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun, 2018, 9(1): 2539.
5.	Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530.
6.	Lau KS, Dennis JW. N-Glycans in cancer progression. Glycobiology, 2008, 18(10): 750-760.
7.	Chiaradonna F, Ricciardiello F, Palorini R. The Nutrient-sensing hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring. Cells, 2018, 7(6): 53.
8.	Akella NM, Ciraku L, Reginato MJ. Fueling the fire: emerging role of thehexosamine biosynthetic pathway in cancer. BMC Biol, 2019, 17(1): 52.
9.	Carvalho-Cruz P, Alisson-Silva F, Todeschini AR, et al. Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Dev Dyn, 2018, 247(3): 481-491.
10.	Munemoto M, Mukaisho KI, Miyashita T, et al. Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid-induced cancer development. Cancer Sci, 2019, 110(8): 2408-2420.
11.	Palorini R, Votta G, Pirola Y, et al. Protein kinase A activation promotes cancer cell resistance to glucose starvation and anoikis. PLoS Genet, 2016, 12(3): e1005931.
12.	Chaveroux C, Sarcinelli C, Barbet V, et al. Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway. Sci Rep, 2016, 6: 27278.
13.	Sharma NS, Saluja AK, Banerjee S. “Nutrient-sensing” and self-renewal: O-GlcNAc in a new role. J Bioenerg Biomembr, 2018, 50(3): 205-211.
14.	Qiao Y, Zhang X, Zhang Y, et al. High glucose stimulates tumorigenesis in hepatocellular carcinoma cells through AGER-dependent O-GlcNAcylation of c-Jun. Diabetes, 2016, 65(3): 619-632.
15.	Taylor RP, Parker GJ, Hazel MW, et al. Glucose deprivation stimulates O-GlcNAc modification of proteins through up-regulation of O-linked N-acetylglucosaminyltransferase. J Biol Chem, 2008, 283(10): 6050-6057.
16.	Moloughney JG, Kim PK, Vega-Cotto NM, et al. mTORC2 responds to glutamine catabolite levels to modulate the hexosamine biosynthesis enzyme GFAT1. Mol Cell, 2016, 63(5): 811-826.
17.	Onodera Y, Nam JM, Bissell MJ. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J Clin Invest, 2014, 124(1): 367-384.
18.	DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 2010, 29(3): 313-324.
19.	Sharma NS, Gupta VK, Garrido VT, et al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest, 2020, 130(1): 451-465.
20.	Liu P, Lu D, Al-Ameri A, et al. Glutamine synthetase promotes tumor invasion in hepatocellular carcinoma through mediating epithelial-mesenchymal transition. Hepatol Res, 2020, 50(2): 246-257.
21.	Efimova EV, Appelbe OK, Ricco N, et al. O-GlcNAcylation enhances double-strand break repair, promotes cancer cell proliferation, and prevents therapy-induced senescence in irradiated tumors. Mol Cancer Res, 2019, 17(6): 1338-1350.
22.	Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol, 2017, 18(7): 452-465.
23.	Ferrer CM, Lu TY, Bacigalupa ZA, et al. O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene, 2017, 36(4): 559-569.
24.	Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature, 2007, 446(7139): 1017-1022.
25.	Leturcq M, Lefebvre T, Vercoutter-Edouart AS. O-GlcNAcylation and chromatin remodeling in mammals: an up-to-date overview. Biochem Soc Trans, 2017, 45(2): 323-338.
26.	Hart GW, Slawson C, Ramirez-Correa G, et al. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem, 2011, 80: 825-858.
27.	Hardiville S, Hart GW. Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab, 2014, 20(2): 208-213.
28.	Zhu Q, Zhou L, Yang Z, et al. O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol, 2012, 29(2): 985-993.
29.	Ma Z, Vosseller K. Cancer metabolism and elevated O-GlcNAc in oncogenic signaling. J Biol Chem, 2014, 289(50): 34457-34465.
30.	苗向霞, 马澜婧, 曹嘉谊, 等. 敲减OGT对肝细胞脂肪合成的作用研究. 中华肝脏病杂志, 2020, 28(2): 147-151.
31.	Phoomak C, Vaeteewoottacharn K, Silsirivanit A, et al. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep, 2017, 7: 43842.
32.	Wang P, Kang D, Cao W, et al. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev, 2012, 28(2): 109-122.
33.	Zhang X, Qiao Y, Wu Q, et al. The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun, 2017, 8: 15280.
34.	Xia H, Chen J, Sekar K, et al. Clinical and metabolomics analysis of hepatocellular carcinoma patients with diabetes mellitus. Metabolomics, 2019, 15(12): 156.
35.	Vasconcelos-Dos-Santos A, Loponte HF, Mantuano NR, et al. Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway. Oncogenesis, 2017, 6(3): e306.
36.	Liu Y, Cao Y, Pan X, et al. O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance. Cell Death Dis, 2018, 9(5): 485.
37.	Zeidan Q, Hart GW. The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways. J Cell Sci, 2010, 123(Pt 1): 13-22.
38.	Mishra S, Ande SR, Salter NW. O-GlcNAc modification: why so intimately associated with phosphorylation? Cell Commun Signal, 2011, 9(1): 1.
39.	Park SY, Kim HS, Kim NH, et al. Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J, 2010, 29(22): 3787-3796.
40.	Miyoshi A, Kitajima Y, Sumi K, et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer, 2004, 90(6): 1265-1273.

1. Villanueva A. Hepatocellular carcinoma. N Engl J Med, 2019, 380(15): 1450-1462.
2. Ding X, He M, Chan AWH, et al. Genomic and epigenomic features of primary and recurrent hepatocellular carcinomas. Gastroenterology, 2019, 157(6): 1630-1645.
3. Wang C, Tong Y, Wen Y, et al. Hepatocellular carcinoma-associated protein TD26 interacts and enhances sterol regulatory element-binding protein 1 activity to promote tumor cell proliferation and growth. Hepatology, 2018, 68(5): 1833-1850.
4. DeWaal D, Nogueira V, Terry AR, et al. Author correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun, 2018, 9(1): 2539.
5. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530.
6. Lau KS, Dennis JW. N-Glycans in cancer progression. Glycobiology, 2008, 18(10): 750-760.
7. Chiaradonna F, Ricciardiello F, Palorini R. The Nutrient-sensing hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring. Cells, 2018, 7(6): 53.
8. Akella NM, Ciraku L, Reginato MJ. Fueling the fire: emerging role of thehexosamine biosynthetic pathway in cancer. BMC Biol, 2019, 17(1): 52.
9. Carvalho-Cruz P, Alisson-Silva F, Todeschini AR, et al. Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Dev Dyn, 2018, 247(3): 481-491.
10. Munemoto M, Mukaisho KI, Miyashita T, et al. Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid-induced cancer development. Cancer Sci, 2019, 110(8): 2408-2420.
11. Palorini R, Votta G, Pirola Y, et al. Protein kinase A activation promotes cancer cell resistance to glucose starvation and anoikis. PLoS Genet, 2016, 12(3): e1005931.
12. Chaveroux C, Sarcinelli C, Barbet V, et al. Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway. Sci Rep, 2016, 6: 27278.
13. Sharma NS, Saluja AK, Banerjee S. “Nutrient-sensing” and self-renewal: O-GlcNAc in a new role. J Bioenerg Biomembr, 2018, 50(3): 205-211.
14. Qiao Y, Zhang X, Zhang Y, et al. High glucose stimulates tumorigenesis in hepatocellular carcinoma cells through AGER-dependent O-GlcNAcylation of c-Jun. Diabetes, 2016, 65(3): 619-632.
15. Taylor RP, Parker GJ, Hazel MW, et al. Glucose deprivation stimulates O-GlcNAc modification of proteins through up-regulation of O-linked N-acetylglucosaminyltransferase. J Biol Chem, 2008, 283(10): 6050-6057.
16. Moloughney JG, Kim PK, Vega-Cotto NM, et al. mTORC2 responds to glutamine catabolite levels to modulate the hexosamine biosynthesis enzyme GFAT1. Mol Cell, 2016, 63(5): 811-826.
17. Onodera Y, Nam JM, Bissell MJ. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J Clin Invest, 2014, 124(1): 367-384.
18. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 2010, 29(3): 313-324.
19. Sharma NS, Gupta VK, Garrido VT, et al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest, 2020, 130(1): 451-465.
20. Liu P, Lu D, Al-Ameri A, et al. Glutamine synthetase promotes tumor invasion in hepatocellular carcinoma through mediating epithelial-mesenchymal transition. Hepatol Res, 2020, 50(2): 246-257.
21. Efimova EV, Appelbe OK, Ricco N, et al. O-GlcNAcylation enhances double-strand break repair, promotes cancer cell proliferation, and prevents therapy-induced senescence in irradiated tumors. Mol Cancer Res, 2019, 17(6): 1338-1350.
22. Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol, 2017, 18(7): 452-465.
23. Ferrer CM, Lu TY, Bacigalupa ZA, et al. O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene, 2017, 36(4): 559-569.
24. Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature, 2007, 446(7139): 1017-1022.
25. Leturcq M, Lefebvre T, Vercoutter-Edouart AS. O-GlcNAcylation and chromatin remodeling in mammals: an up-to-date overview. Biochem Soc Trans, 2017, 45(2): 323-338.
26. Hart GW, Slawson C, Ramirez-Correa G, et al. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem, 2011, 80: 825-858.
27. Hardiville S, Hart GW. Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab, 2014, 20(2): 208-213.
28. Zhu Q, Zhou L, Yang Z, et al. O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol, 2012, 29(2): 985-993.
29. Ma Z, Vosseller K. Cancer metabolism and elevated O-GlcNAc in oncogenic signaling. J Biol Chem, 2014, 289(50): 34457-34465.
30. 苗向霞, 马澜婧, 曹嘉谊, 等. 敲减OGT对肝细胞脂肪合成的作用研究. 中华肝脏病杂志, 2020, 28(2): 147-151.
31. Phoomak C, Vaeteewoottacharn K, Silsirivanit A, et al. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep, 2017, 7: 43842.
32. Wang P, Kang D, Cao W, et al. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev, 2012, 28(2): 109-122.
33. Zhang X, Qiao Y, Wu Q, et al. The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun, 2017, 8: 15280.
34. Xia H, Chen J, Sekar K, et al. Clinical and metabolomics analysis of hepatocellular carcinoma patients with diabetes mellitus. Metabolomics, 2019, 15(12): 156.
35. Vasconcelos-Dos-Santos A, Loponte HF, Mantuano NR, et al. Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway. Oncogenesis, 2017, 6(3): e306.
36. Liu Y, Cao Y, Pan X, et al. O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance. Cell Death Dis, 2018, 9(5): 485.
37. Zeidan Q, Hart GW. The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways. J Cell Sci, 2010, 123(Pt 1): 13-22.
38. Mishra S, Ande SR, Salter NW. O-GlcNAc modification: why so intimately associated with phosphorylation? Cell Commun Signal, 2011, 9(1): 1.
39. Park SY, Kim HS, Kim NH, et al. Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J, 2010, 29(22): 3787-3796.
40. Miyoshi A, Kitajima Y, Sumi K, et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer, 2004, 90(6): 1265-1273.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on the role of hexosamine biosynthesis pathway and O-glycosylation inmetabolism of hepatocellular carcinoma

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