Glutamine synthetase modulates YAP activation by stabilizing LATS under glutamine homeostasis

  • Cell Rep. 2025 Nov 25;44(12):116620. doi: 10.1016/j.celrep.2025.116620.
Siyi Li  1 ,  Ting Ling  2 ,  Yuhan Wang  2 ,  Jing Shi  3 ,  Qiuping Wang  2 ,  Jing Lv  2 ,  Jinghan Li  4 ,  Yu Liu  4 ,  Yi Zhang  1 ,  Changhao Liu  4 ,  Tian Xia  2 ,  Di Chen  2 ,  Wenqi Wang  5 ,  Hong-Xu Liu  6 ,  Hai-Long Piao  7
Affiliations
  • 1. Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China; State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 2. State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 3. State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang 110122, China.
  • 4. Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
  • 5. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
  • 6. Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China. Electronic address: [email protected].
  • 7. Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China; State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang 110122, China. Electronic address: [email protected].
PMID: 41296569 DOI: 10.1016/j.celrep.2025.116620
Abstract

Glutamine homeostasis plays a crucial role in fundamental cellular processes and is often dysregulated in Cancer cells; however, the underlying mechanisms governing this homeostasis remain unclear. Here, we demonstrate that enriched glutamine activates the Hippo pathway. Mechanistically, glutamine synthetase (GS) interacts with LATS1, leading to its downregulation via increased ubiquitin degradation. Glutamine supplementation reduces the expression of GS and stabilizes LATS1, leading to YAP phosphorylation and inhibition. Clinically, GS expression is associated with clinical outcomes and inversely correlated with LATS1 expression and YAP1 phosphorylation. Taken together, these results not only uncover a previously undescribed mechanism by which glutamine homeostasis regulates the Hippo pathway but also suggest a potential therapeutic strategy by targeting glutamine metabolism and key growth-related signaling pathways for Cancer treatment.

Keywords
CP: cancer; CP: metabolism; GS; Hippo pathway; LATS; cancer; glutamine.
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