GALNT8 suppresses breast cancer cell metastasis potential by regulating EGFR O-GalNAcylation

Abstract

Breast cancer represents the most lethal malignancy that threatens the health of females. Metastasis is the fatal hallmark of breast cancer, and current effective therapeutic targets of metastasis are still lacking. Aberrant O-GalNAcylation, which is attributed to alteration of polypeptide N-acetylgalactosaminyl transferases (GALNTs), has been implicated in cancer metastasis. However, GALNTs that drive metastasis in breast cancer and their underlying mechanisms are largely unclear. In the present study, a negative correlation between GALNT8 and the prognosis of breast cancer patients was observed in multiple groups of Gene Expression Omnibus (GEO) datasets. We then constructed a stable GALNT8 knockdown MCF7 cell line and performed transcriptome analysis using RNA sequencing, which revealed that the expression of multiple migration-related genes was changed. GALNT8 was identified as a regulator of epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, ZO-1 and vimentin. Moreover, loss- and gain-of-function GALNT8 assays demonstrated that this glycosyltransferase inhibited the metastatic potential of breast cancer cells. Interestingly, the O-GalNAcylation of EGFR, which is the key factor related to the metastasis cascade, was impacted by GALNT8. Furthermore, our results suggested that the GALNT8-mediated O-GalNAcylation led to the suppression of the EGFR signaling pathway and metastatic potential in breast cancer cells. These results suggested that GALNT8 acts as a tumor suppressor, represses tumor metastasis and inhibits the EMT process through the EGFR signaling pathway. This finding may provide insight into the mechanism by which aberrant O-glycosylation modulates breast cancer metastasis.

Keywords: Breast cancer; E-cadherin; EGFR; GALNT8; O- GalNAcylation.