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FUT8 Promotes Breast Cancer Cell Invasiveness through Remodeling of TGF‐β Receptor Core Fucosylation
Author(s) -
Tu ChengFen,
Wu MengYing,
Lin YuhCharn,
Yang RueyBing
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.953.1
Subject(s) - fucosylation , cancer research , epithelial–mesenchymal transition , metastasis , vasculogenic mimicry , tumor progression , biology , signal transduction , transforming growth factor , microbiology and biotechnology , cancer , fucose , glycoprotein , genetics
Core fucosylation catalyzed by FUT8 (addition of fucose in α‐1,6‐linkage to core N‐acetyl glucosamine of N‐glycans) is critical for signaling receptors involved in many physiological and pathological processes, such as cell growth, differentiation, cell adhesion, inflammation, and tumor metastasis. TGF‐β‐induced epithelial‐mesenchymal transition (EMT) regulates the invasion and metastasis of breast tumors. However, whether receptor core fucosylation affects TGF‐β signaling during breast cancer progression remain largely unknown. In this study, microarray expression profiling analysis was used to identify that FUT8 is highly upregulated in the TGF‐β‐induced EMT, and is associated with the migratory and invasive ability of a number breast carcinoma cell lines. Consistent with these findings, FUT8 expression correlated with poor disease‐free survival and overall survival of breast cancer patients. In addition, gain‐ and loss‐of‐function studies demonstrate that FUT8 overexpression stimulates EMT process while FUT8 knockdown suppresses the invasiveness of highly aggressive MDA‐MB‐231 and 4T1 breast carcinoma cells. Furthermore, we show that TGF‐β receptor is a direct target of FUT8 and its core fucosylation markedly facilitates TGF‐β binding and enhances downstream signaling. Importantly, pharmacological inhibition by a small molecule inhibitor 2F‐peracetyl‐fucoseo or genetic knockdown of FUT8 suppresses the invasive ability of highly metastatic breast cancer cells in vitro and impair their lung metastasis in vivo , respectively. Together, our results reveal a feed‐forward mechanism of FUT8‐mediated receptor core fucosylation that promotes TGF‐β signaling and EMT, thus stimulates breast cancer cell invasion and metastasis. We will further evaluate the in vivo pathological importance of FUT8 during breast cancer progression, and investigate the translational implication by targeting FUT8 on inhibiting breast cancer metastasis.