SLC30A7 phosphorylation by ERK1 promotes esophageal squamous cell carcinoma tumorigenesis via activating MMP2/3/9-β-catenin signaling.

Zinc ions (Zn2+) are crucial for cellular homeostasis, with their intracellular concentrations tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. Zinc dysregulation has been implicated in esophageal squamous cell carcinoma (ESCC), yet the oncogenic roles of zinc transporters remain poorly understood. We herein identify SLC30A7 as a zinc transporter markedly elevated in ESCC and associated with poor prognosis. Genetic deletion of Slc30a7 significantly suppressed 4NQO-induced esophageal tumorigenesis, whereas SLC30A7 knockdown inhibited ESCC cell proliferation, migration, and tumor progression. Mechanistically, ERK1 specifically binds SLC30A7 and phosphorylates SLC30A7 at T297 site, driving the redistribution of zinc (Zn2+) from the cytosol into the Golgi lumen. SLC30A7 cooperates with the zinc metallochaperone ZNG1 to mobilize Golgi-resident zinc toward matrix metalloproteinases MMP2/3/9 activation, leading to E-cadherin degradation, β-catenin nuclear translocation, and MYC transcription. In ESCC PDX models, a tumor-targeted biomimetic ERK inhibitor nanoplatform (Q3ME@PBA-NPs) significantly restrained tumor growth and disrupted the ERK1-SLC30A7-MMP2/3/9-β-catenin-c-Myc axis. These findings reveal a previously unrecognized zinc-dependent oncogenic pathway in ESCC and highlight SLC30A7 as a valuable therapeutic target in cancer.