Abstract
Breast cancer is the most lethal malignancy in women. N-acetylgalactosaminyltransferase 6 (GALNT6) is an enzyme which mediates the initial step of mucin-type O-glycosylation, and has been reported to be involved in mammary carcinogenesis. However, the molecular mechanism of GALNT6 in breast cancer metastasis has not been fully explored. In this study, based on online database analyses and tissue microarrays, the overall survival (OS) of breast cancer patients with high expression of GALNT6 was found to be shorter than those with low expression of GALNT6. Also, high GALNT6 expression was positively correlated with advanced pN stage and pTNM stage. GALNT6 was shown to be able to promote the migration and invasion of breast cancer cells, and enhance the level of mucin-type O-glycosylation of substrates in the supernatants of breast cancer cells. Qualitative mucin-type glycosylomics analysis identified α2M as a novel substrate of GALNT6. Further investigation showed that GALNT6 increased O-glycosylation of α2M, and the following activation of the downstream PI3K/Akt signaling pathway was involved in the promotion of migration and invasion of breast cancer cells. This study identified a new substrate of GALNT6 and provides novel understanding of the role of GALNT6 in promoting metastasis and poor prognosis in breast cancer.
Highlights
Breast cancer is the most common malignancy and the leading cause of cancer-related death in women, with an increasing incidence rate of 3.1% per year [1]
Analysis based on TCGA database which included 1043 breast cancer samples showed that enhanced GALNT6 expression was significantly associated with advanced pN stage (p = 0.033) and advanced pTNM stage (Table 3 and Supplementary Table 2)
This result indicated that GALNT6 might lead to poor prognosis by promoting metastasis in breast cancer
Summary
Breast cancer is the most common malignancy and the leading cause of cancer-related death in women, with an increasing incidence rate of 3.1% per year [1]. Growing studies have reported that abnormal mucin-type O-glycosylation mediated by GALNTs can promote proliferation, survival and metastasis in breast cancer cells. GALNT6 has been shown to promote tumorigenesis and metastasis by catalyzing mucin-type O-glycosylation-mediated stabilization of MUCl and fibronectin (FN) in breast cancer cells [20, 21]. GALNT6-mediated mucin-type Oglycosylation can increase nuclear translocation of estrogen receptor alpha (ERα) in breast cancer [22]. These findings suggest that GALNT6 might play an important role in the prognosis of breast cancer. We identified α2macroglobulin (α2M) as a GALNT6 substrate and showed that GALNT6-mediated α2M glycosylation could promote metastasis via the AKT signaling pathway in breast cancer cells. This study provides novel understanding of GALNT6 in promoting metastasis and poor prognosis of breast cancer
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