O-GlcNAc糖基化修饰在癌症中的调控机制
The Regulatory Mechanism of O-GlcNAc Glycosylation Modification in Cancer
DOI: 10.12677/acm.2025.151126, PDF,    科研立项经费支持
作者: 周美欣, 薛 娟*：西海岸新区区立医院口腔科，山东 青岛；刘 桐*：青岛大学附属泰安市中心医院口腔科，山东 泰安
关键词: O-GlcNA糖基化；分子机制；预后；O-GlcNA Glycosylation； Molecular Mechanism； Prognosis
摘要: O-GlcNAc糖基化是一种可逆的蛋白质翻译后修饰。O-GlcNAc循环失衡在癌症的发生和发展中起着至关重要的作用。因此，探索O-GlcNAc糖基化与肿瘤之间的作用机制对于开发新的靶向治疗方法具有极其重要的意义。本文阐明O-GlcNAc糖基化修饰使细胞能够将营养物质的可用性和细胞代谢与关键细胞过程调节联系起来，其中许多可能在癌症中受到损害。总结O-GlcNAc糖基化调节在肿瘤治疗中的作用，为临床实践中开发新的靶向疗法提供了理论依据。
Abstract: O-GlcNAc glycosylation is a reversible post-translational modification of proteins. The imbalance of O-GlcNAc cycle plays a crucial role in the occurrence and development of cancer. Therefore, exploring the mechanism of action between O-GlcNAc glycosylation and tumors is of great significance for developing new targeted therapies. This article elucidates that O-GlcNAc glycosylation modification enables cells to link the availability of nutrients and cellular metabolism with the regulation of key cellular processes, many of which may be compromised in cancer. Summarizing the role of O-GlcNAc glycosylation regulation in tumor therapy provides a theoretical basis for the development of new targeted therapies in clinical practice.
文章引用：周美欣, 刘桐, 薛娟. O-GlcNAc糖基化修饰在癌症中的调控机制[J]. 临床医学进展, 2025, 15(1): 947-953. https://doi.org/10.12677/acm.2025.151126

参考文献

[1] Olsen, J.V. and Mann, M. (2013) Status of Large-Scale Analysis of Post-Translational Modifications by Mass Spectrometry. Molecular & Cellular Proteomics, 12, 3444-3452. [Google Scholar] [CrossRef] [PubMed]
[2] Yang, X. and Qian, K. (2017) Protein O-GlcNAcylation: Emerging Mechanisms and Functions. Nature Reviews Molecular Cell Biology, 18, 452-465. [Google Scholar] [CrossRef] [PubMed]
[3] Whelan, S.A. and Hart, G.W. (2003) Proteomic Approaches to Analyze the Dynamic Relationships between Nucleocytoplasmic Protein Glycosylation and Phosphorylation. Circulation Research, 93, 1047-1058. [Google Scholar] [CrossRef] [PubMed]
[4] Decourcelle, A., Leprince, D. and Dehennaut, V. (2019) Regulation of Polycomb Repression by O-GlcNAcylation: Linking Nutrition to Epigenetic Reprogramming in Embryonic Development and Cancer. Frontiers in Endocrinology, 10, Article 117. [Google Scholar] [CrossRef] [PubMed]
[5] Hart, G.W., Housley, M.P. and Slawson, C. (2007) Cycling of O-Linked β-N-Acetylglucosamine on Nucleocytoplasmic Proteins. Nature, 446, 1017-1022. [Google Scholar] [CrossRef] [PubMed]
[6] He, X., Hu, X., Wen, G., Wang, Z. and Lin, W. (2023) O-GlcNAcylation in Cancer Development and Immunotherapy. Cancer Letters, 566, Article ID: 216258. [Google Scholar] [CrossRef] [PubMed]
[7] Xie, S., Jin, N., Gu, J., Shi, J., Sun, J., Chu, D., et al. (2016) O‐GlcNAcylation of Protein Kinase a Catalytic Subunits Enhances Its Activity: A Mechanism Linked to Learning and Memory Deficits in Alzheimer’s Disease. Aging Cell, 15, 455-464. [Google Scholar] [CrossRef] [PubMed]
[8] Yang, W.H., Park, S.Y., Nam, H.W., Kim, D.H., Kang, J.G., Kang, E.S., et al. (2008) NFκB Activation Is Associated with Its O-GlcNAcylation State under Hyperglycemic Conditions. Proceedings of the National Academy of Sciences of the United States of America, 105, 17345-17350. [Google Scholar] [CrossRef] [PubMed]
[9] Yuzwa, S.A., Shan, X., Macauley, M.S., Clark, T., Skorobogatko, Y., Vosseller, K., et al. (2012) Increasing O-GlcNAc Slows Neurodegeneration and Stabilizes Tau against Aggregation. Nature Chemical Biology, 8, 393-399. [Google Scholar] [CrossRef] [PubMed]
[10] Yuzwa, S.A. and Vocadlo, D.J. (2014) O-GlcNAc and Neurodegeneration: Biochemical Mechanisms and Potential Roles in Alzheimer’s Disease and Beyond. Chemical Society Reviews, 43, 6839-6858. [Google Scholar] [CrossRef] [PubMed]
[11] Zhang, C., Atasoy, D., Araç, D., Yang, X., Fucillo, M.V., Robison, A.J., et al. (2010) Neurexins Physically and Functionally Interact with GABAA Receptors. Neuron, 66, 403-416. [Google Scholar] [CrossRef] [PubMed]
[12] Zhang, Q., Lenardo, M.J. and Baltimore, D. (2017) 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology. Cell, 168, 37-57. [Google Scholar] [CrossRef] [PubMed]
[13] Zhang, Z., Tan, E.P., VandenHull, N.J., Peterson, K.R. and Slawson, C. (2014) O-GlcNAcase Expression Is Sensitive to Changes in O-GlcNAc Homeostasis. Frontiers in Endocrinology, 5, Article 206. [Google Scholar] [CrossRef] [PubMed]
[14] Zhu, Q., Cheng, X., Cheng, Y., Chen, J., Xu, H., Gao, Y., et al. (2020) O-GlcNAcylation Regulates the Methionine Cycle to Promote Pluripotency of Stem Cells. Proceedings of the National Academy of Sciences of the United States of America, 117, 7755-7763. [Google Scholar] [CrossRef] [PubMed]
[15] Zhu, Y., Wang, Y., Yao, R., Hao, T., Cao, J., Huang, H., et al. (2017) Enhanced Neuroinflammation Mediated by DNA Methylation of the Glucocorticoid Receptor Triggers Cognitive Dysfunction after Sevoflurane Anesthesia in Adult Rats Subjected to Maternal Separation during the Neonatal Period. Journal of Neuroinflammation, 14, Article 6. [Google Scholar] [CrossRef] [PubMed]
[16] Dong, X., Shu, L., Zhang, J., Yang, X., Cheng, X., Zhao, X., et al. (2023) Ogt-Mediated O-GlcNAcylation Inhibits Astrocytes Activation through Modulating NF-κB Signaling Pathway. Journal of Neuroinflammation, 20, Article No. 146. [Google Scholar] [CrossRef] [PubMed]
[17] Zhang, D., Cai, Y., Chen, M., Gao, L., Shen, Y. and Huang, Z. (2015) Ogt-Mediated O-GlcNAcylation Promotes NF-κB Activation and Inflammation in Acute Pancreatitis. Inflammation Research, 64, 943-952. [Google Scholar] [CrossRef] [PubMed]
[18] Yang, Y.R., Kim, D.H., Seo, Y., Park, D., Jang, H., Choi, S.Y., et al. (2015) Elevated O-GlcNAcylation Promotes Colonic Inflammation and Tumorigenesis by Modulating NF-κB Signaling. Oncotarget, 6, 12529-12542. [Google Scholar] [CrossRef] [PubMed]
[19] Motolani, A., Martin, M., Wang, B., Jiang, G., Alipourgivi, F., Huang, X., et al. (2023) Critical Role of Novel O-GlcNAcylation of S550 and S551 on the P65 Subunit of NF-κB in Pancreatic Cancer. Cancers, 15, Article 4742. [Google Scholar] [CrossRef] [PubMed]
[20] Dong, H., Liu, Z. and Wen, H. (2022) Protein O-GlcNAcylation Regulates Innate Immune Cell Function. Frontiers in Immunology, 13, Article 805018. [Google Scholar] [CrossRef] [PubMed]
[21] Ma, Z., Vocadlo, D.J. and Vosseller, K. (2013) Hyper-O-GlcNAcylation Is Anti-Apoptotic and Maintains Constitutive NF-κB Activity in Pancreatic Cancer Cells. Journal of Biological Chemistry, 288, 15121-15130. [Google Scholar] [CrossRef] [PubMed]
[22] Nakagawa, T., Furukawa, Y., Hayashi, T., Nomura, A., Yokoe, S., Moriwaki, K., et al. (2019) Augmented O-GlcNAcylation Attenuates Intermittent Hypoxia-Induced Cardiac Remodeling through the Suppression of NFAT and NF-κB Activities in Mice. Hypertension Research, 42, 1858-1871. [Google Scholar] [CrossRef] [PubMed]
[23] Li, Y., Liu, H., Xu, Q., Du, Y. and Xu, J. (2014) Chitosan Oligosaccharides Block LPS-Induced O-GlcNAcylation of NF-κB and Endothelial Inflammatory Response. Carbohydrate Polymers, 99, 568-578. [Google Scholar] [CrossRef] [PubMed]
[24] Pellegrini, S. and Dusanter‐Fourt, I. (1997) The Structure, Regulation and Function of the Janus Kinases (JAKs) and the Signal Transducers and Activators of Transcription (STATS). European Journal of Biochemistry, 248, 615-633. [Google Scholar] [CrossRef] [PubMed]
[25] Liongue, C., O’Sullivan, L.A., Trengove, M.C. and Ward, A.C. (2012) Evolution of JAK-STAT Pathway Components: Mechanisms and Role in Immune System Development. PLOS ONE, 7, e32777. [Google Scholar] [CrossRef] [PubMed]
[26] Du, X., Wang, B., Liu, X., Liu, X., He, Y., Zhang, Q., et al. (2017) Comparative Transcriptome Analysis of Ovary and Testis Reveals Potential Sex-Related Genes and Pathways in Spotted Knifejaw Oplegnathus Punctatus. Gene, 637, 203-210. [Google Scholar] [CrossRef] [PubMed]
[27] Zhang, Z., Ma, P., Li, Q., Xiao, Q., Sun, H., Olasege, B.S., et al. (2018) Exploring the Genetic Correlation between Growth and Immunity Based on Summary Statistics of Genome-Wide Association Studies. Frontiers in Genetics, 9, Article 393. [Google Scholar] [CrossRef] [PubMed]
[28] Auernhammer, C.J., Chesnokova, V., Bousquet, C. and Melmed, S. (1998) Pituitary Corticotroph SOCS-3: Novel Intracellular Regulation of Leukemia-Inhibitory Factor-Mediated Proopiomelanocortin Gene Expression and Adrenocorticotropin Secretion. Molecular Endocrinology, 12, 954-961. [Google Scholar] [CrossRef] [PubMed]
[29] Herrera, S.C. and Bach, E.A. (2019) JAK/STAT Signaling in Stem Cells and Regeneration: From Drosophila to Vertebrates. Development, 146, dev167643. [Google Scholar] [CrossRef] [PubMed]
[30] Kornfeld, J. (2008) The Different Functions of Stat5 and Chromatin Alteration through Stat5 Proteins. Frontiers in Bioscience, 13, 6237-6254. [Google Scholar] [CrossRef] [PubMed]
[31] Briscoe, J., Guschin, D. and Müller, M. (1994) Signal Transduction: Just Another Signalling Pathway. Current Biology, 4, 1033-1035. [Google Scholar] [CrossRef] [PubMed]
[32] Images SSMAFM.
https://smart.servier.com
[33] Bond, M.R. and Hanover, J.A. (2015) A Little Sugar Goes a Long Way: The Cell Biology of O-GlcNAc. Journal of Cell Biology, 208, 869-880. [Google Scholar] [CrossRef] [PubMed]
[34] Love, D.C. and Hanover, J.A. (2005) The Hexosamine Signaling Pathway: Deciphering the “O-GlcNAc Code”. Science’s STKE, 2005, re13. [Google Scholar] [CrossRef] [PubMed]
[35] Krämer, O.H. and Moriggl, R. (2012) Acetylation and Sumoylation Control STAT5 Activation Antagonistically. JAK-STAT, 1, 203-207. [Google Scholar] [CrossRef] [PubMed]
[36] Liu, J., Qian, C. and Cao, X. (2016) Post-Translational Modification Control of Innate Immunity. Immunity, 45, 15-30. [Google Scholar] [CrossRef] [PubMed]
[37] Enchev, R.I., Schulman, B.A. and Peter, M. (2014) Protein Neddylation: Beyond Cullin-Ring Ligases. Nature Reviews Molecular Cell Biology, 16, 30-44. [Google Scholar] [CrossRef] [PubMed]
[38] Alleyn, M., Breitzig, M., Lockey, R. and Kolliputi, N. (2018) The Dawn of Succinylation: A Posttranslational Modification. American Journal of Physiology-Cell Physiology, 314, C228-C232. [Google Scholar] [CrossRef] [PubMed]
[39] Van Nguyen, T., Angkasekwinai, P., Dou, H., Lin, F., Lu, L., Cheng, J., et al. (2012) Sumo-Specific Protease 1 Is Critical for Early Lymphoid Development through Regulation of STAT5 Activation. Molecular Cell, 45, 210-221. [Google Scholar] [CrossRef] [PubMed]
[40] Rani, A. and Murphy, J.J. (2016) STAT5 in Cancer and Immunity. Journal of Interferon & Cytokine Research, 36, 226-237. [Google Scholar] [CrossRef] [PubMed]
[41] Chen, P., Chi, J. and Boyce, M. (2018) Functional Crosstalk among Oxidative Stress and O-GlcNAc Signaling Pathways. Glycobiology, 28, 556-564. [Google Scholar] [CrossRef] [PubMed]
[42] Kang, J.G., Park, S.Y., Ji, S., Jang, I., Park, S., Kim, H.S., et al. (2009) O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation. Journal of Biological Chemistry, 284, 34777-34784. [Google Scholar] [CrossRef] [PubMed]
[43] Taylor, R.P., Geisler, T.S., Chambers, J.H. and McClain, D.A. (2009) Up-Regulation of O-GlcNAc Transferase with Glucose Deprivation in HepG2 Cells Is Mediated by Decreased Hexosamine Pathway Flux. Journal of Biological Chemistry, 284, 3425-3432. [Google Scholar] [CrossRef] [PubMed]
[44] Xiao, Z., Dai, Z. and Locasale, J.W. (2019) Metabolic Landscape of the Tumor Microenvironment at Single Cell Resolution. Nature Communications, 10, Article No. 3763. [Google Scholar] [CrossRef] [PubMed]
[45] Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K.J. and Werb, Z. (2020) Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis. Nature Communications, 11, Article No. 5120. [Google Scholar] [CrossRef] [PubMed]
[46] Pan, D. and Jia, D. (2021) Application of Single-Cell Multi-Omics in Dissecting Cancer Cell Plasticity and Tumor Heterogeneity. Frontiers in Molecular Biosciences, 8, Article 757024. [Google Scholar] [CrossRef] [PubMed]
[47] Jiang, Y., Guo, H., Tong, T., Xie, F., Qin, X., Wang, X., et al. (2022) lncRNA Lnc-POP1-1 Upregulated by VN1R5 Promotes Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma through Interaction with MCM5. Molecular Therapy, 30, 448-467. [Google Scholar] [CrossRef] [PubMed]
[48] Su, Y., Wu, C., Chang, Y., Li, L., Chen, Y., Jia, X., et al. (2022) USP17L2-SIRT7 Axis Regulates DNA Damage Repair and Chemoresistance in Breast Cancer Cells. Breast Cancer Research and Treatment, 196, 31-44. [Google Scholar] [CrossRef] [PubMed]
[49] Kayagaki, N., Webster, J.D. and Newton, K. (2024) Control of Cell Death in Health and Disease. Annual Review of Pathology: Mechanisms of Disease, 19, 157-180. [Google Scholar] [CrossRef] [PubMed]
[50] Shi, L., Tang, X., Qian, M., Liu, Z., Meng, F., Fu, L., et al. (2018) A Sirt1-Centered Circuitry Regulates Breast Cancer Stemness and Metastasis. Oncogene, 37, 6299-6315. [Google Scholar] [CrossRef] [PubMed]
[51] Ferrer, C.M., Lu, T.Y., Bacigalupa, Z.A., Katsetos, C.D., Sinclair, D.A. and Reginato, M.J. (2016) O-glcNAcylation Regulates Breast Cancer Metastasis via SIRT1 Modulation of FOXM1 Pathway. Oncogene, 36, 559-569. [Google Scholar] [CrossRef] [PubMed]
[52] Yan, W., Cao, M., Ruan, X., Jiang, L., Lee, S., Lemanek, A., et al. (2022) Cancer-Cell-Secreted miR-122 Suppresses O-GlcNAcylation to Promote Skeletal Muscle Proteolysis. Nature Cell Biology, 24, 793-804. [Google Scholar] [CrossRef] [PubMed]
[53] Yang, W.H., Kim, J.E., Nam, H.W., Ju, J.W., Kim, H.S., Kim, Y.S., et al. (2006) Modification of P53 with O-Linked N-Acetylglucosamine Regulates P53 Activity and Stability. Nature Cell Biology, 8, 1074-1083. [Google Scholar] [CrossRef] [PubMed]

为你推荐