Abstract
Basal-like breast cancer is characterized by an aggressive clinical outcome and presence of metastasis, for which effective therapies are unavailable. We have previously shown that chondroitin 4-O-sulfotransferase-1 (C4ST-1) controls the invasive properties of the basal-like breast cancer cell line BT-549 by inducing matrix metalloproteinase (MMP) expression through the N-cadherin/β-catenin pathway. Here we report that C4ST-1 controls the proliferation of BT-549 cells via the MMP-dependent cleavage of syndecan-1. Syndecan-1 is a membrane-bound proteoglycan associated with an aggressive phenotype and poor prognosis in breast cancer. In addition, the cleavage of syndecan-1 at a specific juxtamembrane cleavage site is implicated in the pathophysiological response in breast cancer. Knockout of C4ST-1 remarkably suppressed both the cleavage of syndecan-1 and proliferation of BT-549 cells. Kinases (AKT1, ERK1/2, PI3K, and STAT3) comprising cancer proliferative pathways are phosphorylated in C4ST-1 knockout cells at a level similar to that in parental BT-549 cells, whereas levels of phosphorylated S6 kinase and SUMOylated AKT (hyperactivated AKT observed in breast cancer) decreased in C4ST-1 knockout cells. An MMP inhibitor, GM6001, suppressed the small ubiquitin-like modifier (SUMO) modification of AKT, suggesting that cleavage of syndecan-1 by MMPs is involved in the SUMO modification of AKT. Forced expression of the cytoplasmic domain of syndecan-1, which is generated by MMP-dependent cleavage, increased the SUMO modification of AKT and global protein SUMOylation. Furthermore, syndecan-1 C-terminal domain-expressing BT-549 cells were more proliferative and sensitive to a potent SUMOylation inhibitor, tannic acid, compared with BT-549 cells transfected with an empty expression vector. These findings assign new functions to the C-terminal fragment of syndecan-1 generated by MMP-dependent proteolysis, thereby broadening our understanding of their physiological importance and implying that the therapeutic inhibition of syndecan-1 cleavage could affect the progression of basal-like breast cancer.
Highlights
Chondroitin sulfate (CS), a glycosaminoglycan (GAG), is present on the cell surface and in the extracellular matrix (Sugahara et al, 2003)
We investigated whether matrix metalloproteinase (MMP) are involved in the proliferation of BT-549 cells (Figure 1G) because the loss of chondroitin 4-O-sulfotransferase-1 (C4ST-1) expression decreases the expression of matrix metalloproteinase 9 (MMP9), which is a target gene of β-catenin (Nadanaka et al, 2018)
We previously showed that CS produced by C4ST-1 induces the expression of MMP9 mediated via the N-cadherin/β-catenin pathway and upregulates the invasive activity of BT-549 cells
Summary
Chondroitin sulfate (CS), a glycosaminoglycan (GAG), is present on the cell surface and in the extracellular matrix (Sugahara et al, 2003). There is ample evidence for the pro-tumorigenic role of CS in the enhancement of cell proliferation, cell motility, and metastasis. CS is a linear sulfated polymer consisting of repeating disaccharide units of glucuronic acid (GlcUA) and N-acetylgalactosamine (GalNAc) [-GlcUA-GalNAc-]n. During the synthesis of the CS backbone, various sulfotransferases catalyze sulfation. Chondroitin-4-O-sulfotransferase (C4ST-1) is involved in the biosynthesis of A-units [GlcUA-GalNAc(4O-sulfate)] and E-disaccharide units [GlcUA-GalNAc(4,6-Odisulfates)] (Nadanaka et al, 2008; Mikami and Kitagawa, 2013; Nadanaka et al, 2020). Specific sulfation patterns are believed to underlie the distinct functional roles of CS under physiological conditions and in tumor development and progression (Nadanaka et al, 2018)
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