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TAB3 O-GlcNAcylation promotes metastasis of triple negative breast cancer
Tao Tao1,2, Zhixian He3, Zhiming Shao1
1Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
Abstract:
O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Although previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNActransferase are linked to the incidence of metastasis in triple negative breast cancer (TNBC) patients, the molecular basis behind this is not fully understood. In this study, we have determined that the TAK1 binding protein 3 (TAB3) was O-GlcNAcylated at Ser408 by OGT in the TNBC, which was required for its Thr404 phosphorylation, TAK1 activation and downstream nuclear factor kappa B (NF-κB) activation in TNBC. O-GlcNAcylation of TAB3 was induced by p38 MAPK and it in turn enhances the TAK1 mediated p38MAPK activation, which forms the positive feedback loop in TAB3mediated NF-κB activation. In TNBC, TAB3O-GlcNAcylationmediated cell migration and invasion by activating its downstream NF-κB. The expression of TAB3 O-GlcNAcylation increased in TNBC patients, and it was significantly correlated with poor prognoses of the patients. Our study provides insights into the mechanism of TAB3 regulating activity and suggests its important implications in TNBC metastasis.
Insights
O-linked N-acetylglucosamine (O-GlcNAc) modification of TAK1 binding protein 3 (TAB3) drives triple-negative breast cancer (TNBC) metastasis by activating the NF-κB pathway. Increased TAB3 O-GlcNAcylation correlates with poor TNBC patient prognosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- O-GlcNAcylation is a post-translational modification regulating protein function.
- Elevated O-GlcNAcylation and O-GlcNAc transferase (OGT) are linked to triple-negative breast cancer (TNBC) metastasis.
- The precise molecular mechanisms underlying this association remain unclear.
Purpose of the Study:
- To elucidate the role of TAB3 O-GlcNAcylation in TNBC metastasis.
- To identify the specific O-GlcNAcylation site on TAB3 and its functional consequences.
- To investigate the signaling pathways regulated by TAB3 O-GlcNAcylation in TNBC.
Main Methods:
- Western blotting to detect protein modifications and activations.
- Immunoprecipitation to identify protein interactions.
- Cell migration and invasion assays.
- Analysis of patient data for correlation studies.
Main Results:
- TAB3 is O-GlcNAcylated by OGT at Ser408 in TNBC, which is essential for its phosphorylation at Thr404.
- O-GlcNAcylated TAB3 activates TAK1 and downstream NF-κB signaling.
- A positive feedback loop involving p38 MAPK enhances TAB3-mediated NF-κB activation.
- TAB3 O-GlcNAcylation promotes TNBC cell migration and invasion.
- Increased TAB3 O-GlcNAcylation expression in TNBC patients correlates with poor prognosis.
Conclusions:
- TAB3 O-GlcNAcylation at Ser408 is a critical driver of TNBC metastasis.
- The TAB3-TAK1-NF-κB signaling axis, modulated by O-GlcNAcylation, is a key pathway in TNBC progression.
- TAB3 O-GlcNAcylation represents a potential therapeutic target for TNBC.
