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

Tao Tao,Zhixian He,Zhiming Shao,Haojie Lu

doi:10.18632/oncotarget.8182

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.

Highlights

Breast cancer is becoming the main causes of cancer death among women
TAB1 was undetected in all cells, but TAB2were expressed in all five cell lines
To investigate whether the expression of Transforming growth factor β activated kinase 1 (TAK1) binding protein 3 (TAB3) was associated with breast cancer cell migration and invasion, stable MDA-MB-231 or MDA-MB-468 cells transfected with TAB3 expression or knockdown plasmid were established (Figure 1A)

Summary

Introduction

Breast cancer is becoming the main causes of cancer death among women. Breast cancer is classified into 4 subtypes, including Lumina A, Lumina B, HER-2+ and Basel-like ( termed triple negative breast cancer, TNBC), based on the molecular characteristics of the cancer genetics. TNBC is the most prevalent one which remains incurable despite of recent therapeutic advances [1]. It was known that chronic inflammation play an essential role in cancer development and metastasis. The major link between chronic inflammation and breast cancer metastasis is mediated by activation of nuclear factor-κB (NF-κB) [2]. Pro-inflammatory cytokine interleukin-1β (IL-1β), which is secreted by adipose tissue or macrophages, promotes breast cancer metastasis by constitutive and deregulated activation of NF-κB signaling pathway [3]

Methods

Results

Conclusion