ST3GAL1 regulates cancer cell migration through crosstalk between EGFR and neuropilin-1 signaling

Metastasis is a major cause of cancer-related morbidity and mortality. The overexpression of the sialyltransferase ST3GAL1 in breast cancer correlates with metastasis. However, the molecular mechanisms underlying the effect of ST3GAL1 on cell movement are poorly understood. We identified neuropilin-1/NRP1 as a substrate for ST3GAL1. Gene expression analysis revealed that recurrence-free survival (p = 0.0046) and distant metastasis-free survival (p = 0.0003) were significantly shorter in the ST3GAL1^HighNRP1^High cohort than in the both-low subgroup. We demonstrated that the ST3GAL1-mediated sialylation of NRP1 results in increased binding affinity toward EGFR at the molecular level. At the cellular level, ST3GAL1 silencing impaired cell migration and wound healing ability, which was linked to reduced activities of CAPN2 as a consequence of diminished EGF/EGFR signaling. These data establish a function for the ST3GAL1-mediated sialylation of NRP1, leading to increased EGF/EGFR downstream signaling and enhanced tumor cell motility. Furthermore, ST3GAL1 silencing augmented the sensitivity to cetuximab-mediated cell lysis. Our findings provide novel insight into the mechanisms underlying the function of ST3GAL1 in promoting tumor cell migration through the EGFR/NRP1 pathway. Our results suggest that ST3GAL1 may represent a valuable target for strategies aimed at inhibiting tumor migration.