GlcNAcylation Plays an Essential Role in Breast Cancer Metastasis

Abstract

GlcNAcylation, a dynamic posttranslational modification, is involved in a wide range of biological processes and some human diseases. Although there is emerging evidence that some tumor-associated proteins are modified by GlcNAcylation, the role of GlcNAcylation in tumor progression remains unclear. Here, we show that GlcNAcylation enhances the migration/invasion of breast cancer cells in vitro and lung metastasis in vivo. The decrease of cell surface E-cadherin is the molecular mechanism underlying GlcNAcylation-induced breast cancer metastasis. p120 and β-catenin, but not E-cadherin, are GlcNAcylated; the GlcNAcylation of p120 and β-catenin might play roles in the decrease of cell surface E-cadherin. Moreover, immunohistochemistry analysis indicated that the global GlcNAcylation level in breast tumor tissues is elevated significantly as compared with that in the corresponding adjacent tissues; further, GlcNAcylation was significantly enhanced in metastatic lymph nodes compared with their corresponding primary tumor tissues. This is the first report to clearly elucidate the roles and mechanisms whereby GlcNAcylation influences the malignant properties of breast cancer cells. These results also suggest that GlcNAcylation might be a potential target for the diagnosis and therapy of breast cancer. Cancer Res; 70(15);

O-GlcNAcylation is increased in prostate cancer tissues and enhances malignancy of prostate cancer cells

“…The nucleocytoplasmic OGT (ncOGT) contains 13 TPRs, the mitochondrial OGT (mOGT) contains a mitochondrial-targeting sequence at its N-terminus and nine TPRs, and the shortest OGT isoform (sOGT) contains only two TPRs. Previous studies have indicated that the expression of OGT is increased in certain cancer types, but the OGT isoforms were not discriminated in these reports (11,12,14,22). Here, we detected by IB the expression of OGT using specific antibodies that recognize all three OGT isoforms, and the results showed that ncOGT and mOGT, but not sOGT, are detectable in all tested cell lines (Fig.…”

“…We previously reported that increased O-GlcNAcylation reduces the level of the cell surface protein E-cadherin, which has the potential to enhance cell invasion and metastasis in breast cancer cells (12). The binding of the E-cadherin/catenin complex to the cytoskeleton is essential for strong cell-cell adhesion (26), and we demonstrated that an increase in the O-GlcNAc level inhibits the formation of the E-cadherin/catenin/cytoskeleton complex (12).…”

“…As a glycolytic pathway, HBP can enhance the level of UDP-GlcNAc, and thus, the activity of OGT, which may lead to an increase in the global O-GlcNAc level (summed over all proteins) in cancer cells. We have previously demonstrated that the global O-GlcNAc level is increased in breast, lung and colon cancer tissues as compared to respective adjacent tissues (11,12). In addition, other research groups have shown that O-GlcNAcylation is increased in breast, prostate and pancreatic cancer cell lines (13-15).…”

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

“…EMT involves loss of epithelial markers such as E-cadherin and gain of mesenchymal markers such as vimentin and N-cadherin (79,81). We and others have found that reducing hyper-OGlcNAcylation in cancers increases expression of the epithelial marker E-cadherin and decreases expression of the mesenchymal marker vimentin, whereas elevating O-GlcNAc decreases expression of the epithelial marker E-cadherin in breast and liver cancer (8,15,78). The loss of E-cadherin is regarded as a key step in initiation of EMT (79), and transcription factors, including Snail, E47, and Zeb, can directly bind to the promoter of E-cadherin, thereby repressing its expression (82).…”

“…Emerging evidence suggests that hyper-O-GlcNAcylation in cancers may be involved in tumor invasion and metastasis. Whereas increasing hyper-O-GlcNAcylation enhances the migration/invasion of breast and liver cancer cells, lowering hyper-O-GlcNAcylation by knockdown of OGT inhibits tumor invasion and metastasis in vivo and in vitro in breast and prostate cancer cells (7)(8)(9)78). The mechanisms by which hyper-O-GlcNAcylation may regulate tumor invasion and metastasis are only beginning to be understood.…”