SYNJ2BP plays an important role in breast cancer metastasis. However, the molecular mechanism associated with the function of SYNJ2BP in metastasis remains unclear. In this study, we investigated the role of SYNJ2BP in tumor metastasis and established the associated underlying mechanism. Over-expression of SYNJ2BP promoted both cell migration and invasion. In contrast, silencing SYNJ2BP caused the suppression of cell migration and invasion. SYNJ2BP increased the levels of phosphorylation for AKT and GSK3β, which could be inhibited by the PI3K inhibitor, LY294002, and the GSK3β inhibitor, LiCl, and regulated the accumulation of SNAI1 in the nucleus and the expression of the SNAI1 target gene, E-cadherin (EMT m... More
SYNJ2BP plays an important role in breast cancer metastasis. However, the molecular mechanism associated with the function of SYNJ2BP in metastasis remains unclear. In this study, we investigated the role of SYNJ2BP in tumor metastasis and established the associated underlying mechanism. Over-expression of SYNJ2BP promoted both cell migration and invasion. In contrast, silencing SYNJ2BP caused the suppression of cell migration and invasion. SYNJ2BP increased the levels of phosphorylation for AKT and GSK3β, which could be inhibited by the PI3K inhibitor, LY294002, and the GSK3β inhibitor, LiCl, and regulated the accumulation of SNAI1 in the nucleus and the expression of the SNAI1 target gene, E-cadherin (EMT marker). It is known that the stability of PTEN is regulated by ubiquitination. However, in this study, we additionally demonstrated that SYNJ2BP mediated the degradation of PTEN protein by the lysosome-pathway and induced the activation of PI3K/AKT signaling by promoting the co-localization of PTEN with autophagy-lysosomes and the expression of LC3-II and p62. In vivo study, the overexpression of SYNJ2BP significantly increased the metastasis of 4T1 cells in BALB/c mice. In addition, SYNJ2BP was highly expressed in breast carcinoma (p = 0.0031), but not in normal breast tissue, while analysis of tissue samples taken from SNAI1-positive human breast cancers showed a significant correlation between the expression of SYNJ2BP and that of p-AKT (p < 0.005). Collectively, our data identified a tumor inducer, SYNJ2BP, which could activate the PI3K/AKT/GSK3β/SNAI1 signaling pathway through the lysosomemediated degradation of PTEN, and promote both EMT and tumor metastasis during the progression of breast cancer.
