Frequently amplified SHANK2 promotes esophageal squamous cell carcinoma progression through the DVL/YAP axis.

SHANK2 is crucial for neuronal synapse development and has been implicated in certain tumors; however, its role in esophageal squamous cell carcinoma (ESCC) remains underexplored. In this study, the expression and prognostic significance of SHANK2 in ESCC were assessed through bioinformatics analyses and immunohistochemical staining. We examined the relationship between SHANK2 expression and genetic alterations across multiple ESCC datasets. The effects of SHANK2 on cell proliferation, migration, and invasion were evaluated using cell-based assays. Potential SHANK2-interacting proteins were identified via co-immunoprecipitation followed by mass spectrometry and further validated using immunoprecipitation and immunoblotting. Additionally, we investigated the in vivo role of SHANK2 in ESCC progression using tumor xenograft mouse models. Our findings demonstrated that SHANK2 expression was significantly elevated in ESCC tissues, with high levels correlating with poor patient prognosis. Genetic amplification of SHANK2 was frequently observed in ESCC samples. SHANK2 promoted the proliferation, motility, and epithelial-mesenchymal transition of ESCC cells. Mechanistically, SHANK2 may activate the YAP signaling through competitive binding with DVL2, thereby facilitating malignant progression. In vivo studies indicated that targeting YAP signaling can mitigate SHANK2-induced ESCC growth. Taken together, SHANK2 is upregulated in ESCC and activates YAP signaling by interacting with DVL2, contributing to tumor progression. The SHANK2/DVL/YAP axis presents a potential therapeutic target for ESCC.