The spread of tumors significantly worsens outcomes for individuals with gastric cancer. RNA-binding proteins (RBPs) play key roles in cancer spread, although their specific contributions to gastric cancer remain underexplored. In this work, we identified ESRP1, an epithelial-specific RBP, as a critical modulator of metastatic behavior in gastric cancer cells. Levels of ESRP1 show an inverse association with both distant and lymph node metastases in affected patients. Experiments confirmed that ESRP1 suppresses cell migration and invasion in gastric cancer models both in laboratory settings and animal studies. At the molecular level, ESRP1 facilitates alternative splicing of exon 11 in CLSTN1 pre-mRNA. The resulting shorter isoform of CLSTN1 strengthens the interaction between E-cadherin and β-catenin, while enhancing ubiquitination and subsequent degradation of β-catenin protein, ultimately restraining migratory and invasive properties of gastric cancer cells. This investigation underscores ESRP1's suppressive influence on gastric cancer spread and uncovers additional mechanistic insights. Findings suggest that ESRP1 and CLSTN1 could serve as promising targets for interventions against metastatic gastric cancer.
