Increasing HER2 a2,6 sialylation facilitates gastric cancer progression and resistance via the akt and ERK pathways

Abstract

Upregulated ß-galactoside a2,6-sialyltransferase I (ST6Gal-I) expression reportedly occurs in many cancers and is correlated with metastasis and poor prognosis. However, the mechanisms by which ST6Gal-I facilitates gastric cancer progression remain poorly understood. Trastuzumab is exclusively used in human epidermal growth factor receptor 2 (HER2)+ gastric cancers; however, most advanced HER2+ gastric cancers develop trastuzumab resistance. Herein, we identified HER2 as an ST6Gal-I substrate and showed that HER2 a2,6 sialylation confers protection against trastuzumab-mediated apoptosis. SGC7901 cancer cell models in which ST6Gal-I was overexpressed or knocked down were constructed, revealing that ST6Gal-I overexpression induced high HER2 sialylation levels and increased cell viability and invasion compared to those in the vector cell line under serum starvation; ST6Gal-I knockdown had the opposite effects. ST6Gal-I overexpression also potentiated cell cycle arrest in the G2/S phase to reduce drug sensitivity. In addition, FACS analysis revealed that high ST6Gal-I levels increased resistance to trastuzumab-induced apoptosis, accompanied by decreased caspase-3 levels. However, the ST6Gal-I knockdown cell line revealed increased caspase-3 levels and evident apoptosis compared with those in the vector cell line. Although ST6Gal-I overexpression increased HER2 sialylation, corresponding to decreased HER2 phosphorylation, high a2,6-sialylation enhanced Akt and ERK phosphorylation levels compared to those in the vector cell line; ST6Gal-I knockdown had the opposite effects. Collectively, these results implicated a functional role of ST6Gal-I in promoting tumor cell progression and trastuzumab resistance.