2. Academic Validation
  3. O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth

O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth

  • Cell Death Differ. 2025 Oct 6. doi: 10.1038/s41418-025-01591-8.
Bingyi Lin # 1,  Junjie Zhou # 1,  Didi Geng # 2,  Siyuan Chai 1,  Xuanming Zhang 1,  Zengle Zhang 1,  Jiating Hu 1,  Qin Tang 3,  Xiaoming Chen 4,  Wen Yi 5 6,  Liming Wu 7 8
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
  • 2 Department of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 3 Department of General Surgery, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 4 School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China. wyi@zju.edu.cn.
  • 6 Department of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China. wyi@zju.edu.cn.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China. wlm@zju.edu.cn.
  • 8 Department of General Surgery, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. wlm@zju.edu.cn.
  • # Contributed equally.
PMID: 41053177 DOI: 10.1038/s41418-025-01591-8
Abstract

The tumor microenvironment is an immunosuppressive niche that contributes to tumor growth by downregulating immune cell functions or restraining immune cell infiltration. The underlying mechanisms are not still poorly understood. Here, we demonstrate that O-linked N-acetylglucosamine (O-GlcNAcylation), a prevalent form of protein glycosylation, contributes to establishing the immunosuppressive niche through regulating the metabolic and non-metabolic functions of uridine diphosphate glucose dehydrogenase (UGDH). Tumor cells carrying O-GlcNAcylation-deficient UGDH showed reduced xenograft tumor growth and improved survival in mice. Cytometry by time-of-flight (CyTOF) analysis suggests UGDH O-GlcNAcylation negatively correlates with cytotoxic CD8+ T cell infiltration. O-GlcNAcylation on serine 350 of UGDH is located within the UDP-binding domain, and the subsequent extensive all-atom molecular dynamics simulations reveal that O-GlcNAcylation reinforces hydrogen-bonding interaction and enzymatic activity of UGDH, leading to enhanced hyaluronic acid (HA) synthesis in the extracellular matrix. Moreover, O-GlcNAcylation of UGDH reduces CD8+ T cell infiltration by decreasing the chemokine CXCL10 expression. Specifically, O-GlcNAcylation enhances UGDH interaction with KPNA2 to compete with STAT1, and suppresses translocation of STAT1 into the nucleus, thereby transcriptionally downregulating CXCL10 expression. Thus, our study identifies UGDH O-GlcNAcylation as a key regulator of tumor immunity and further suggests a potential strategy for enhancing immunotherapy.

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