Abstract
Caveolin-1 (Cav-1) is an important structural protein of caveolae and plays an oncogene-like role by influencing protein glycosylation in hepatocellular carcinoma (HCC) cells. However, the mechanism by which Cav-1 promotes invasion and metastasis capacity has not been completely clarified. In this study, we demonstrate that Pofut1 is a fucosyltransferase induced by Cav-1. Mouse Hepa1-6 HCC cells lacking Cav-1 expression exhibited low transcription levels of Pofut1, whereas strong Pofut1 expression was found in high-metastasis-potential Hca-F cells with high levels of Cav-1. Cav-1 activated MAPK signaling and promoted phosphorylation of the transcription factors CREB, Sp1, HNF4A and c-Myc, which bound to the Pofut1 promoter region to induce its transcription. As Notch signaling receptors can be modified with O-fucose by Pofut1, we further showed that Cav-1-induced upregulation of Pofut1 expression activated the Notch pathway and thus enhanced invasion and metastasis by mouse HCC cells in vitro and in vivo. Collectively, our findings reveal a novel mechanism by which Cav-1 promotes tumor metastasis by upregulating expression of Pofut1, suggesting that Cav-1 may function as a new biomarker for HCC.
Highlights
Caveolin-1 (Cav-1), a major structural protein of caveolae, has been implicated in many cellular processes, including lipid transport, signal transduction, and tumor progression
We demonstrate that Cav-1 upregulates expression of Pofut[1] by activating the mitogen-activated protein kinase (MAPK) pathway to increase the phosphorylation levels of downstream transcription factors that bind to the promoter region of Pofut[1]
Cav-1 is an essential structural and functional component of caveolae that is widely expressed in eukaryotes; this protein is mainly distributed in terminally differentiated cells, such as myocytes, endothelial cells, epithelial cells, and fibroblasts
Summary
Caveolin-1 (Cav-1), a major structural protein of caveolae, has been implicated in many cellular processes, including lipid transport, signal transduction, and tumor progression. There is a growing body of evidence that Cav-1 can regulate protein glycosylation[4,5,6]. Previous studies performed by our laboratory showed that Cav-1 promotes lymphatic metastasis of mouse hepatocellular carcinoma (HCC) cells by inducing CD147 glycosylation[8,9]. Cav-1 can promote sialylation of HCC cells by enhancing the expression of glycosyltransferase ST6Gal-1, increasing the adhesion ability of these cells[10]. The above evidence indicates that Cav-1 exerts an oncogene-like effect in HCC by affecting glycosylation levels, glycosylation-related protein localization, and glycosyltransferase expression. Overexpression of certain fucosyltransferases (FUTs) in tumor cells leads to an increased level of fucosylation, resulting in abnormal cell proliferation, the epithelial–mesenchymal
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