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E3 ubiquitin ligases are key tumour regulators and potential therapeutic targets in gastric cancer. This study investigates whether von Hippel\u2013Lindau (VHL), an E3 ligase, regulates the stability of synaptotagmin 11 (SYT11) protein in gastric cancer cells. VHL overexpression decreased SYT11 protein expression without affecting SYT11 mRNA expression. Notably, VHL overexpression decreased the half\u2010life of SYT11 protein, and MG132, a proteasome inhibitor, reversed SYT11 degradation by VHL. Immunoprecipitation confirmed the binding of SYT11 to VHL, and VHL knockdown resulted in reduced SYT11 ubiquitination and degradation. Transcriptome sequencing revealed the downregulation of serine peptidase inhibitor kazal type 1 (SPINK1) by VHL and its upregulation by SYT11. VHL downregulated the expression of SYT11, which subsequently led to the inhibition of SPINK1 expression. Furthermore, SPINK1 knockdown inhibited the growth and invasion of gastric cancer cells, mirroring VHL overexpression effects. The inhibition of growth and invasion in MKN1 and SNU484 cells by VHL was rescued by the overexpression of SYT11 and SPINK1. These findings demonstrate that the proteasome\u2010dependent degradation of SYT11 by VHL and the subsequent reduction in SPINK1 expression inhibit gastric cancer cell growth and invasion.<\/jats:p>","DOI":"10.1111\/jcmm.70658","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T08:24:33Z","timestamp":1751012673000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["VHL\u2010Mediated SYT11 Degradation Suppresses Gastric Cancer Cell Growth and Invasion Through Downregulation of SPINK1"],"prefix":"10.1111","volume":"29","author":[{"given":"Ji Su","family":"Yu","sequence":"first","affiliation":[{"name":"Genomic Medicine Research Center Korea Research Institute of Bioscience and Biotechnology  Daejeon Korea"},{"name":"Department of Biochemistry and Molecular Biology Korea University College of Medicine  Seoul 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