Functional inactivation of oligosaccharyltransferase a isoform suppresses tumor metastasis.

Oligosaccharyltransferase (OST), which is a multi-membrane protein complex that catalyzes asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum (ER), is a potential target to eradicate refractory cancer. Mammals express two distinct OST isoforms (OST-A and OST-B) that exhibit different acceptor site specificity to maximize N-glycosylation efficiency; however, the role of individual OST isoforms in tumor progression is not fully understood. Here, using mouse melanoma model, we showed that gene-edited knockout of either one of the OST isoforms did not compromise subcutaneous tumor growth, while their co-expression was required for efficient experimental lung metastasis. We further showed that the cytosolic N-terminal region of Stt3a, which is the catalytic subunit of OST-A, was critical for the N-glycosylation reaction and lung metastasis. This study opens a novel avenue for selective manipulation of OST-A activity, which might offer potential therapeutic strategies for metastatic cancers.