Research Progress of Glucuronyl C5-Epimerase in Cancers: A Review

© 2026 by the Authors. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

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Abstract

Glucuronyl C5-epimerase (GLCE) is a key enzyme in heparan sulfate biosynthesis. Mice with a whole-genome knockout of GLCE exhibit embryonic lethality, highlighting its essential roles in growth and development and its involvement in processes such as obesity, neurogenesis, and immune regulation. Interestingly, GLCE exerts similar or even opposite effects in different cancers. The functional complexity of GLCE in cancers positions it as a promising biomarker and therapeutic target. However, current understanding of the roles and underlying mechanisms of GLCE in various cancers remains limited. This article reviews and discusses the functions and molecular mechanisms of GLCE in different cancers.

References

Feyerabend TB, Li JP, Lindahl U, et al., 2006, Heparan Sulfate C5-Epimerase Is Essential for Heparin Biosynthesis in Mast Cells. Nature Chemical Biology, 2(4): 195–196.

Jia J, Maccarana M, Zhang X, et al., 2009, Lack of L-Iduronic Acid in Heparan Sulfate Affects Interaction with Growth Factors and Cell Signaling. Journal of Biological Chemistry, 284(23): 15942–15950.

Li JP, Gong F, Hagner-Mcwhirter A, et al., 2003, Targeted Disruption of a Murine Glucuronyl C5-Epimerase Gene Results in Heparan Sulfate Lacking L-Iduronic Acid and in Neonatal Lethality. Journal of Biological Chemistry, 278(31): 28363–28366.

Ledin J, Staatz W, Li JP, et al., 2004, Heparan Sulfate Structure in Mice with Genetically Modified Heparan Sulfate Production. Journal of Biological Chemistry, 279(41): 42732–42741.

Bülow HE, Hobert O, 2004, Differential Sulfations and Epimerization Define Heparan Sulfate Specificity in Nervous System Development. Neuron, 41(5): 723–736.

Qin Y, Ke J, Gu X, et al., 2015, Structural and Functional Study of D-Glucuronyl C5-Epimerase. Journal of Biological Chemistry, 290(8): 4620–4630.

He F, Jiang H, Peng C, et al., 2023, Hepatic Glucuronyl C5-Epimerase Combats Obesity by Stabilising GDF15. Journal of Hepatology, 79(3): 605–617.

Li J, Fang J, Qin Y, et al., 2014, GLCE Regulates PC12 Cell Neuritogenesis Induced by Nerve Growth Factor through Activating SMAD/ID3 Signalling. Biochemical Journal, 459(2): 405–415.

Jiang J, Zhan X, Xu G, et al., 2021, Glycolysis- and Immune-Related Novel Prognostic Biomarkers of Ewing’s Sarcoma: Glucuronic Acid Epimerase and Triosephosphate Isomerase 1. Aging (Albany NY), 13(13): 17516–17535.

Chanalaris A, Clarke H, Guimond SE, et al., 2019, Heparan Sulfate Proteoglycan Synthesis Is Dysregulated in Human Osteoarthritic Cartilage. American Journal of Clinical Pathology, 189(3): 632–647.

Grigorieva E, Eshchenko T, Rykova VI, et al., 2008, Decreased Expression of Human D-Glucuronyl C5-Epimerase in Breast Cancer. International Journal of Cancer, 122(5): 1172–1176.

Prudnikova TY, Mostovich LA, Domanitskaya NV, et al., 2010, Antiproliferative Effect of D-Glucuronyl C5-Epimerase in Human Breast Cancer Cells. Cancer Cell International, 10: 27.

Kunnas T, Solakivi T, Määttä K, et al., 2016, Glucuronic Acid Epimerase (GLCE) Variant rs3865014 (A>G) Is Associated with BMI, Blood Hemoglobin, Hypertension, and Cerebrovascular Events, the TAMRISK Study. Annals of Human Genetics, 80(6): 332–335.

Belyavskaya VA, Prudnikova TY, Domanitskaya NV, et al., 2017, GLCE rs3865014 (Val597Ile) Polymorphism Is Associated with Breast Cancer Susceptibility and Triple-Negative Breast Cancer in Siberian Population. Gene, 628: 224–229.

Mostovich LA, Prudnikova TY, Kondratov AG, et al., 2012, The TCF4/β-Catenin Pathway and Chromatin Structure Cooperate to Regulate D-Glucuronyl C5-Epimerase Expression in Breast Cancer. Epigenetics, 7(8): 930–939.

Prudnikova TY, Mostovich LA, Kashuba VI, et al., 2012, miRNA-218 Contributes to the Regulation of D-Glucuronyl C5-Epimerase Expression in Normal and Tumor Breast Tissues. Epigenetics, 7(10): 1109–1114.

Prudnikova TY, Soulitzis N, Kutsenko OS, et al., 2013, Heterogeneity of D-Glucuronyl C5-Epimerase Expression and Epigenetic Regulation in Prostate Cancer. Cancer Medicine, 2(5): 654–661.

Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. A Cancer Journal for Clinicians, 71(3): 209–249.

Li Y, Huo J, He J, et al., 2021, LncRNA MONC Suppresses the Malignant Phenotype of Endometrial Cancer Stem Cells and Endometrial Carcinoma Cells by Regulating the miR-636/GLCE Axis. Cancer Cell International, 21(1): 331.

Rosenberg EE, Prudnikova TY, Zabarovsky ER, et al., 2014, D-Glucuronyl C5-Epimerase Cell Type Specifically Affects Angiogenesis Pathway in Different Prostate Cancer Cells. Tumor Biology, 35(4): 3237–3245.

Grigorieva EV, Strokotova AV, Ernberg I, et al., 2024, Differential Regulation of Heparan Sulfate Biosynthesis in Fibroblasts Cocultured with Normal vs. Cancerous Prostate Cells. Frontiers in Immunology, 15: 1440623.

He K, Gan WJ, 2023, Wnt/β-Catenin Signaling Pathway in the Development and Progression of Colorectal Cancer. Cancer Management and Research, 15: 435–448.

Ghiselli G, Agrawal A, 2005, The Human D-Glucuronyl C5-Epimerase Gene Is Transcriptionally Activated through the Beta-Catenin-TCF4 Pathway. Biochemical Journal, 390(Pt 2): 493–499.

Klein AP, 2021, Pancreatic Cancer Epidemiology: Understanding the Role of Lifestyle and Inherited Risk Factors. Nature Reviews Gastroenterology & Hepatology, 18(7): 493–502.

Liu T, Joshu CE, Lu J, et al., 2023, External Validation of Genetically Predicted Protein Biomarkers for Pancreatic Cancer Risk Using Aptamer-Based Plasma Levels: A Prospective Analysis in the Atherosclerosis Risk in Communities Study. International Journal of Cancer, 153(6): 1201–1216.

Rudin CM, Brambilla E, Faivre-Finn C, et al., 2021, Small-Cell Lung Cancer. Nature Reviews Disease Primers, 7(1): 3.

Grigorieva EV, Prudnikova TY, Domanitskaya NV, et al., 2011, D-Glucuronyl C5-Epimerase Suppresses Small-Cell Lung Cancer Cell Proliferation in Vitro and Tumour Growth in Vivo. British Journal of Cancer, 105(1): 74–82.

Chen C, Xie L, Ren T, et al., 2021, Immunotherapy for Osteosarcoma: Fundamental Mechanism, Rationale, and Recent Breakthroughs. Cancer Letters, 500: 1–10.

Huang W, Xiao Y, Wang H, et al., 2022, Identification of Risk Model Based on Glycolysis-Related Genes in the Metastasis of Osteosarcoma. Front Endocrinol (Lausanne), 13: 1047433.

Northcott PA, Robinson GW, Kratz CP, et al., 2019, Medulloblastoma. Nature Reviews Disease Primers, 5(1): 11.

Zhou X, Zhao H, 2023, FAIM2 Is Correlated with Metastasis of Medulloblastoma through Bioinformatics Analysis. Medicine (Baltimore), 102(16): e33591.

Ushakov VS, Tsidulko AY, De La Bourdonnaye G, et al., 2017, Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation. International Journal of Molecular Science, 18(11): 2301.

Lah TT, Novak M, Breznik B, 2020, Brain Malignancies: Glioblastoma and Brain Metastases. Seminars in Cancer Biology, 60: 262–273.

Sokolov DK, Shevelev OB, Khotskina AS, et al., 2023, Dexamethasone Inhibits Heparan Sulfate Biosynthetic System and Decreases Heparan Sulfate Content in Orthotopic Glioblastoma Tumors in Mice. International Journal of Molecular Science, 24(12): 10243.

Tsibulnikov S, Fayzullina D, Karlina I, et al., 2023, Ewing Sarcoma Treatment: A Gene Therapy Approach. Cancer Gene Therapy, 30(8): 1066–1071.

Jia F, Liu L, Weng Q, et al., 2023, Glycolysis-Metabolism-Related Prognostic Signature for Ewing Sarcoma Patients. Molecular Biotechnology, 66(10): 2882–2896.

Wen J, Yi L, Wan L, et al., 2023, Prognostic Value of GLCE and Infiltrating Immune Cells in Ewing Sarcoma. Heliyon, 9(9): e19357.

Jing X, Wu J, Ning J, et al., 2025, D-Glucuronyl C5-Epimerase Binds to EGFR to Suppress Kidney Fibrosis. Advanced Science (Weinh), 12(40): e16216.

Reijmers RM, Groen RW, Kuil A, et al., 2011, Disruption of Heparan Sulfate Proteoglycan Conformation Perturbs B-Cell Maturation and APRIL-Mediated Plasma Cell Survival. Blood, 117(23): 6162–6171.

Debarnot C, Monneau YR, Roig-Zamboni V, et al., 2019, Substrate Binding Mode and Catalytic Mechanism of Human Heparan Sulfate D-Glucuronyl C5 Epimerase. Proceedings of the National Academy of Sciences of the United States of America, 116(14): 6760–6765.

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