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  3. A pathological role of O-GlcNAcylation-driven TR11B production and function in lung adenocarcinoma

A pathological role of O-GlcNAcylation-driven TR11B production and function in lung adenocarcinoma

  • Dev Cell. 2025 Sep 3:S1534-5807(25)00530-1. doi: 10.1016/j.devcel.2025.08.010.
Shiyu Qiu 1,  Lifang Ma 2,  Keke Yu 3,  Xin Xu 4,  Xiao Zhang 4,  Wenjun Yu 2,  Kai Wang 5,  Xiaoting Tian 4,  Yayou Miao 4,  Yikun Wang 1,  Wanxin Guo 1,  Xiangfei Xue 1,  Jiangtao Cui 4,  Xuewen Yu 6,  Rui Kang 7,  Qianjun Zhou 8,  Yongchun Yu 9,  Daolin Tang 10,  Jiayi Wang 11
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 2 Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 3 Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 4 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 5 Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6 Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 7 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8 Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: zhouqj@sjtu.edu.cn.
  • 9 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: yyc2166@sjtu.edu.cn.
  • 10 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.
  • 11 Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: jiayi.wang@sjtu.edu.cn.
PMID: 40930100 DOI: 10.1016/j.devcel.2025.08.010
Abstract

Cytokines link inflammation to tumorigenesis, but the role of post-translational modifications in regulating their function within the extra-tumoral environment remains poorly defined. Here, we identify tumor-derived tumor necrosis factor (TNF) receptor superfamily member 11B (TR11B) as a key driver of lung adenocarcinoma (LUAD) progression and therapeutic resistance. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation at serine 151 stabilizes TR11B and facilitates its interaction with the membrane protein EPS15 homology domain-containing protein 1 (EHD1), promoting cyclin dependent kinase 2 (CDK2) phosphorylation and cell cycle progression. Clinically, elevated O-GlcNAcylated TR11B correlates with advanced LUAD. Genetic deletion of OGT suppresses tumor development in LUAD mouse models. Importantly, celecoxib, an U.S. Food and Drug Administration (FDA)-approved drug, inhibits O-GlcNAcylation and exerts antitumor effects. These findings reveal a pathological role for cytokine O-GlcNAcylation in LUAD and identify this axis as a potential therapeutic target.

Keywords

O-GlcNAcylation; cell cycle; cytokines; lung adenocarcinoma; tumorigenesis.

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