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
  • 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: [email protected].
  • 9. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: [email protected].
  • 10. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 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: [email protected].
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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