FOXP2 suppresses gastric cancer progression by transcriptionally repressing FBXW2 via WASL degradation

Gastric cancer (GC) is an aggressive malignancy with poor clinical outcome. F-box and WD repeat domain-containing protein 2 (FBXW2), a substrate receptor of the SKP1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complex, has been implicated in tumor suppression across multiple malignancies; however, its role in GC progression remains undefined. Here, we integrated transcriptomic analyses using the TNMplot database and clinical specimens to demonstrate that FBXW2 expression was significantly downregulated in GC tissues, with low FBXW2 levels correlating closely with poor survival in GC patients. Functional characterization via gain- and loss-of-function strategies revealed that FBXW2 overexpression potently inhibited proliferation, cancer stem cell phenotype, migratory capacity, and invasive potential in human GC cell lines. Consistently, xenograft tumor models showed that FBXW2 overexpression delayed tumor growth and suppresses pulmonary metastasis. FBXW2 silencing promoted malignant progression both in vitro and in vivo. Label-free quantitative proteomics combined with mechanistic investigations identified WASP-like actin nucleation-promoting factor (WASL), a key regulator of cytoskeletal dynamics, as a direct downstream target of FBXW2. FBXW2 physically interacted with WASL and facilitated its ubiquitination-dependent proteasomal degradation. Ectopic WASL expression abrogated FBXW2-mediated suppression of GC cell viability and metastatic potential. Chromatin immunoprecipitation-PCR and DNA Pull Down analyses further revealed that Forkhead box P2 (FOXP2), a transcription factor frequently upregulated in GC, directly bound the FBXW2 promoter to repress its transcription, linking epigenetic dysregulation to FBXW2 downregulation in malignant tissues. Collectively, this study establishes FBXW2 as a critical tumor suppressor in GC, operating through ubiquitin-mediated degradation of WASL to inhibit cancer progression. Targeting the FOXP2-FBXW2-WASL axis may represent a promising therapeutic strategy for combating GC malignancy.