WDR72 Drives Esophageal Squamous Cell Carcinoma Progression by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a high rate of recurrence and metastasis, necessitating the identification of novel therapeutic targets. WD repeat-containing protein 72 (WDR72) has been linked to various cancers, but its specific biological function and underlying mechanism in ESCC remain largely unexplored. Herein, we investigated whether WDR72 promotes ESCC progression by suppressing autophagy via the PI3K/Akt/mTOR pathway. We first analyzed WDR72 expression using GEO (GSE213565) and validated using the GEPIA public databases. WDR72 mRNA/protein levels were then examined in patient-derived ESCC tissues and cell lines (EC109, KYSE150). Loss- and gain-of-function models (shRNA knockdown and pcDNA3.1-WDR72 overexpression) were used to evaluate proliferation, clonogenicity, apoptosis, migration/invasion, and autophagy. PI3K/Akt/mTOR activity was examined by measuring PI3K, p-Akt, and p-mTOR, with pathway dependence tested using the dual PI3K/mTOR inhibitor BEZ235. In vivo tumor growth and metastasis were analyzed in xenograft and lung metastasis models. We found that WDR72 was significantly overexpressed in ESCC tissues and cell lines. WDR72 depletion suppressed malignant phenotypes in vitro and substantially inhibited tumor growth and metastasis in vivo. Mechanistically, WDR72 overexpression activated the PI3K/Akt/mTOR pathway (indicated by elevated p-Akt and p-mTOR levels) and concurrently suppressed autophagy (evidenced by decreased Beclin-1 and LC3-II/LC3-I ratio, and increased P62). Notably, the PI3K/mTOR inhibitor BEZ235 abolished the pro-malignant effects and reversed the autophagy suppression induced by WDR72 overexpression. Collectively, our findings establish that WDR72 acts as an oncogene in ESCC by promoting proliferation, survival, and metastasis via activating the PI3K/Akt/mTOR signaling to suppress autophagy.