TAK1结合蛋白3（TAB3）O-GlcNAc糖基化可促进三阴性乳腺癌转移

　　单个N-乙酰葡萄糖胺（GlcNAc）在蛋白质的丝氨酸或苏氨酸残基的羟基氧原子上进行连接称之为蛋白质O-GlcNAc糖基化，细胞核和细胞质中的蛋白质均可进行O-GlcNAc糖基化修饰。O-GlcNAc修饰广泛参与细胞周期、基因转录、蛋白质翻译及加工、信号转导和细胞应激反应等多种细胞生命活动。O-GlcNAc修饰异常可导致糖尿病、心血管疾病、肿瘤和阿尔茨海默病等多种疾病的发生。肿瘤组织中蛋白质O-GlcNAc糖基化异常与肿瘤细胞的增殖和转移等密切相关。

　　2016年3月18日，复旦大学和南通大学在《Oncotarget》发表的研究发现：转化生长因子β（TGFβ）活化激酶1（TAK1）结合蛋白3（TAB3）O-GlcNAc糖基化可促进三阴性乳腺癌转移。

Oncotarget. 2016 Mar 18. [Epub ahead of print]

TAB3 O-GlcNAcylation promotes metastasis of triple negative breast cancer.

Tao T, He Z, Shao Z, Lu H.

Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.

Department of Chemistry, Fudan University, Shanghai 200433, P.R. China.

Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P.R. China.

Key Laboratory of Glycoconjugates Research Ministry of Public Health, Fudan University, Shanghai 200032, P.R. China.

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 activationand downstream nuclear factor kappa B (NF-κB) activation in TNBC. O-GlcNAcylation of TAB3 was induced by p38 MAPK and it in turnenhances 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.

KEYWORDS: O-glcNAcylation; TAB3; metastasis; triple negative breast cancer

PMID: 27009840

DOI: 10.18632/oncotarget.8182