To the Editor: O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a crucial post-translational modification regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Dysregulation of O-GlcNAcylation has been implicated in numerous disease processes, particularly in tumorigenesis. Lung cancer is the leading cause of cancer-related mortality worldwide. Most patients with lung cancer are diagnosed at an advanced stage, which poses grave risks to their lives. O-GlcNAcylation facilitates cancer cell adaption to adverse environments, playing a critical role in the onset and progression of lung cancer. This article provides a brief overview of O-GlcNAcylation properties and recent advancements in its study across various diseases, with a particular focus on lung cancer.
The discovery of protein O-GlcNAcylation dates back to the early 1980s. It involves the covalent attachment of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of nuclear and cytoplasmic proteins. UDP-GlcNAc is synthesized through the hexosamine biosynthesis pathway (HBP). HBP is a process found in eukaryotic organisms that involves a series of enzymatic reactions leading to the synthesis of UDP-GlcNAc from glucose.[1] The key enzymes involved in HBP, include glucosamine-6-phosphate acetyltransferase (GFAT or GFPT), GlcNAc-1-phosphotransferase (GNPNAT1), phosphoglucomutase 3 (PGM3), and UDP-N-acetylhexosamine pyrophosphorylase 1 (UAP1). Mammals possess paralogues GFAT1 (GFPT1) and GFAT2 (GFPT2). UDP-GlcNAc serves as both a substrate and precursor for diverse glycosylation modifications, prominently O-GlcNAcylation [Supplementary Figure 1, http://links.lww.com/CM9/C182].
Unlike traditional glycosylation modifications, O-GlcNAcylation does not lead to the formation of complex branched glycans. It is regulated by two enzymes OGT and OGA, which dynamically modify numerous proteins within the nucleus, cytoplasm, and mitochondria. OGT can be categorized into three subtypes based on its structure: nucleocytoplasmic or full-length OGT, mitochondrial OGT, and short OGT. This multifunctional enzyme contains distinct domains: a tetratricopeptide repeat (TPR) domain at the N-terminus of OGT for protein interactions, an N-terminal domain for substrate binding, an intermediate domain with undefined function, and a C-terminal domain for catalyzing UDP-GlcNAc transfer.[2] OGA consists of an N-terminal OGA catalytic domain and a C-terminal histone acetyltransferase (HAT) domain.[3] In mammals, long isoform of O-GlcNAcase (OGA-L) (with HAT) is expressed in the nucleus and cytoplasm, while short isoform of O-GlcNAcase (OGA-S) (without HAT) is primarily found in the nucleus and lipid droplets [Supplementary Figure 2, http://links.lww.com/CM9/C182].
O-GlcNAcylation is extensively researched in cancer, where dysregulated levels can disrupt crucial signaling pathways, promoting tumor development.[4] Elevated O-GlcNAcylation in various cancers, such as gastric, colorectal, pancreatic ductal adenocarcinoma, breast, cervical, prostate, and bladder cancers, drives cancer progression and enhances drug resistance. Conversely, decreased levels of O-GlcNAcylation lead to diverse effects, such as enhanced survival, reduced drug resistance, inhibited metastasis, and decreased inflammation across different cancer types. Beyond cancer, elevated O-GlcNAcylation impacts various physiological systems and diseases. In pregnancy, it facilitates successful embryo implantation. Conversely, in the heart, it leads to calcium dysregulation, contractile dysfunction, arrhythmias, and cardiomyopathy, particularly prominent in diabetes-induced heart failure.[5] In the immune system, elevated O-GlcNAcylation can inappropriately activate immune cells, leading to inflammatory responses and immune-related diseases. In the liver, it disrupts mitochondrial oxidation, resulting in hepatic lipid accumulation. In the brain, elevated O-GlcNAcylation is linked to reduced brain size and neuronal ischemia-reperfusion injury.[6] Conversely, neurodegenerative diseases exhibit significantly reduced levels of O-GlcNAcylation in brain tissues, affecting memory consolidation. Decreased O-GlcNAcylation levels in the liver may lead to inadequate hepatocyte differentiation, potentially promoting liver fibrosis [Supplementary Figure 3, http://links.lww.com/CM9/C182].
Lung cancer represents the leading cause of cancer-related mortality worldwide, exhibiting sex disparities. Smoking significantly amplifies this risk. Additionally, occupational exposure, human papilloma virus (HPV) infection, and compromised health status further elevate the risk. Globally, preventive strategies for lung cancer primarily revolve around smoking avoidance and cessation, adoption of a healthy diet, and maintenance of an active lifestyle. Among patients undergoing lung cancer screening, chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, tuberculosis, and asthma are the most common comorbidities. Various diagnostic modalities such as deep neural networks and radiomics based algorithms provide effective tools for evaluating the risk of lung cancer and differentiating subtypes.
The etiology of lung cancer remains unclear; however, glucose metabolism and O-GlcNAcylation play significant regulatory roles in its initiation and progression. O-GlcNAcylation regulates the migration and invasion potential of lung cancer cells, with identified O-GlcNAcylation sites within critical proteins. One such protein, 68-Kda SRC-associated protein in mitosis, an RNA-binding protein predominantly located in the nucleus, undergoes O-GlcNAcylation in highly invasive lung cancer cells. Additionally, GFPT2 has been identified as a pivotal regulatory factor in tumor metabolic reprogramming. Nuclear factor-κB (NF-κB), a transcription factor, stimulates the expression of GFPT2, whereas sirtuin 6 (SIRT6) inhibits it. Alterations in GFPT2 expression significantly impact the migratory and invasive potential of lung cancer cells.[7] Moreover, the transient receptor potential melastatin 7 (TRPM7)/O-GlcNAc pathway regulates the stability of caveolin-1 and c-Myc proteins in lung cancer cells by interfering with their O-GlcNAcylation and proteasomal degradation. It eventually affects the motility and metastatic behavior of lung cancer cells by modulating the stability of the two proteins.[8] Silencing OGT reduces the expression of epithelial mesenchymal transition (EMT) markers like N-cadherin and Slug in interleukin (IL)-6-treated lung cancer cells, thereby suppressing migration and invasion. OGT also mediates the phosphorylation of signal transducer and activator of transcription 3 (STAT3), impacting EMT-related signaling pathways. These findings underscore the therapeutic potential of targeting the OGT-STAT3 axis in IL-6-induced lung cancer EMT. The proliferation and growth of lung cancer are associated with abnormalities in glucose metabolism. IL-8, a chemokine, upregulates the expression of glucose transporter 3 and GFAT1 in lung cancer cells, promoting glucose uptake and increasing O-GlcNAcylation.[9] KRAS/liver kinase B1 (LKB1) co-mutations in lung cancer upregulate GFPT2 and PGM3. Targeting PGM3 inhibits tumor growth effectively.[10] Under specific conditions, tumor growth factor-β (TGF-β) promotes tumorigenesis by upregulating HBP genes such as GFPT2 in cancer-associated fibroblasts. O-GlcNAcylation of SMAD family member 4 (SMAD4) reduces the activity of TGF-β. In small cell lung cancer, DEK proto-oncogene (DEK) and 5′-3′ Exoribonuclease 2 (XRN2), both transcription factors, positively regulate OGT, thereby influencing disease progression. Lysine-specific demethylase 2 directly facilitates the ubiquitination of OGT, promoting its degradation via the proteasome pathway. Phosphoribosyl pyrophosphate synthetase 1, a critical enzyme in de novo nucleotide synthesis, promotes the development of lung cancer through O-GlcNAc modification.[11] The tumor suppressor miR-7-5p inhibits OGT expression by directly binding to its 3′-untranslated region (UTR). Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein that regulates immune responses. Inhibiting GFAT1 may potentially enhance the anti-tumor immune response by modulating PD-L1 stability. The tubulin tyrosine ligase like 5 (TTLL5)–GFAT1–transient activator-binding protein 1 (TAB 1) complex activates p38/mitogen-activated protein kinase (MAPK), promoting autophagy for tumor cell survival during glucose deprivation.[12] During glucose deprivation, lung cancer cells reroute glycolytic products to activate phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB), crucial for their survival. Normal primary cells trigger intrinsic fail-safe mechanisms like oncogene-induced senescence (OIS) in response to cellular stress caused by oncogenic factors. Mutations in KRAS, particularly the G12D mutation, enhance glucose supply, inhibiting cellular OIS and allowing tumor cells to evade normal cell cycle regulation [Figure 1].
Figure 1.
Effects of O-GlcNAcylation on the migration, proliferation, and immune evasion of lung cancer cells. Dysregulated cellular uptake of extracellular calcium ions and glucose influences the activity of HBP and proteins modified via O-GlcNAcylation, resulting in imbalanced O-GlcNAcylation levels. DEK: DEK proto-oncogene; G: O-GlcNAcylation; GFAT1: Glutamine-fructose-6-phosphate amidotransferase 1; GFPT2: Glutamine-Fructose-6-Phosphate Transaminase 2; GLUT3: Glucose transporter 3; HBP: Hexosamine biosynthesis pathway; IL: Interleukin; LSD2: Lysine-specific demethylase 2; miR: MicroRNA; LKB1: Liver kinase B1; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor-κB; O-GlcNAcylation: O-linked β-N-acetylglucosaminylation; OGT: O-GlcNAc transferase; OIS: Oncogene-induced senescence; PD-L1: Programmed death ligand 1; PGM3: Phosphoglucomutase 3; PI3K: Phosphoinositide 3-kinase; PKB: Protein kinase B; PRPS1: Phosphoribosyl pyrophosphate synthetase 1; p-STAT3: Phosphorylation of signal transducer and activator of transcription 3; SAM68: SRC-associated protein in mitosis, 68 kDa; SIRT6: Sirtuin 6; SMAD6: SMAD Family Member 6; TAB1: Transient Activator-Binding protein 1; TGF-β: Tumor growth factor-β; TRPM7: Transient Receptor Potential Melastatin 7; TTLL5: Tubulin Tyrosine Ligase Like 5; XRN2: 5'-3' Exoribonuclease 2.
Lung cancer is characterized by its high heterogeneity and malignancy, underscoring the increasing emphasis on biomarkers for prognosis and treatment response. Targeting O-GlcNAcylation, particularly through OGT inhibition, shows promise in attenuating cancer progression and metastasis by modulating apoptosis. Anti-angiogenic agents like OGT 2115 and tranilast disrupt tumor vasculature, inhibiting growth and spread. Moreover, targeting OGT and the TRPM7/O-GlcNAc pathway provides additional therapeutic avenues for managing lung cancer metastasis. OGT overexpression correlates with tumor invasion and metastasis, suggesting OGT as a promising therapeutic target. Elevated levels of enzymes like GFAT1, GFPT2, and TAB 1 are associated with poorer prognosis in lung adenocarcinoma, while increased OGT and Src associated in mitosis, 68 kDa (SAM68) levels are linked to advanced disease and reduced survival. Inhibiting these enzymes, particularly GFAT1 and GFPT2, holds the potential for attenuating tumor growth and enhancing chemotherapy sensitivity. Given technological advancements and ongoing research efforts, O-GlcNAcylation is increasingly recognized as a pivotal focus in lung cancer investigations. Future endeavors capitalizing on insights garnered from O-GlcNAcylation research could lead to the development of innovative treatment modalities aimed at improving outcomes for lung cancer patients. Potential strategies include targeted inhibition of specific O-GlcNAcylation-associated enzymes, exploring synergistic combination therapies with established treatments to enhance efficacy, and investigating supplementary pathways and targets implicated in lung cancer advancement and metastasis. Ultimately, sustained research endeavors in this domain offer the prospect of advancing more efficacious and personalized therapies for individuals afflicted with lung cancer.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 82000052), Sichuan Science and Technology Program (2022YFS0632), and the joint foundation of Luzhou Government and Southwest Medical University (Nos. 2020LZXNYDJ11, 2021LZXNYD-J25).
Conflicts of interest
None.
Supplementary Material
Footnotes
How to cite this article: Jiang JX, Huang XC, Feng JG, Liu L, Liu YL, Jia J. O-linked β-N-acetylglucosaminylation in lung cancer and beyond: A multidimensional perspective. Chin Med J 2025;138:355–357. doi: 10.1097/CM9.0000000000003329
References
- 1.Liu X Blaženović I Contreras AJ Pham TM Tabuloc CA Li YH, et al. Hexosamine biosynthetic pathway and O-GlcNAc-processing enzymes regulate daily rhythms in protein O-GlcNAcylation. Nat Commun 2021;12:4173. doi: 10.1038/s41467-021-24301-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zhang N Jiang H Zhang K Zhu J Wang Z Long Y, et al. OGT as potential novel target: Structure, function and inhibitors. Chem Biol Interact 2022;357:109886. doi: 10.1016/j.cbi.2022.109886. [DOI] [PubMed] [Google Scholar]
- 3.Muha V Authier F Szoke-Kovacs Z Johnson S Gallagher J McNeilly A, et al. Loss of O-GlcNAcase catalytic activity leads to defects in mouse embryogenesis. J Biol Chem 2021;296:100439. doi: 10.1016/j.jbc.2021.100439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lu Q, Zhang X, Liang T, Bai X. O-GlcNAcylation: An important post-translational modification and a potential therapeutic target for cancer therapy. Mol Med 2022;28:115. doi: 10.1186/s10020-022-00544-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Prakoso D Lim SY Erickson JR Wallace RS Lees JG Tate M, et al. Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart. Cardiovasc Res 2022;118:212–225. doi: 10.1093/cvr/cvab043. [DOI] [PubMed] [Google Scholar]
- 6.Shao MS Yang X Zhang CC Jiang CY Mao Y Xu WD, et al. O-GlcNAcylation in ventral tegmental area dopaminergic neurons regulates motor learning and the response to natural reward. Neurosci Bull 2022;38:263–274. doi: 10.1007/s12264-021-00776-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Szymura SJ Zaemes JP Allison DF Clift SH D’Innocenzi JM Gray LG, et al. NF-κB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer. Cell Commun Signal 2019;17:24. doi: 10.1186/s12964-019-0335-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Luanpitpong S Rodboon N Samart P Vinayanuwattikun C Klamkhlai S Chanvorachote P, et al. A novel TRPM7/O-GlcNAc axis mediates tumour cell motility and metastasis by stabilising c-Myc and caveolin-1 in lung carcinoma. Br J Cancer 2020;123:1289–1301. doi: 10.1038/s41416-020-0991-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Shimizu M, Tanaka N. IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells. Oncogene 2019;38:1520–1533. doi: 10.1038/s41388-018-0533-4. [DOI] [PubMed] [Google Scholar]
- 10.Lee H, Cai F, Kelekar N, Velupally NK, Kim J. Targeting GM3 as a novel therapeutic strategy in KRAS/LKB1 Co-mutant lung cancer. Cells 2022;11:176. doi: 10.3390/cells11010176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Chen L Zhou Q Zhang P Tan W Li Y Xu Z, et al. Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation. Nat Chem Biol 2024;20:19–29. doi: 10.1038/s41589-023-01354-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Wei S Zhao Q Zheng K Liu P Sha N Li Y, et al. GFAT1-linked TAB 1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation. Cell Discov 2022;8:77. doi: 10.1038/s41421-022-00423-0. [DOI] [PMC free article] [PubMed] [Google Scholar]