Bisecting N-Acetylglucosamine on EGFR Inhibits Malignant Phenotype of Breast Cancer via Down-Regulation of EGFR/Erk Signaling
Bisecting N-Acetylglucosamine on EGFR Inhibits Malignant Phenotype of Breast Cancer via Down-Regulation of EGFR/Erk Signaling
复制标题
EGFR 上的 N-乙酰氨基葡萄糖二等分通过下调 EGFR/Erk 信号传导抑制乳腺癌的恶性表型
DOI：
10.3389/fonc.2020.00929
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发表时间：
2020-06-16
影响因子：
4.7
通讯作者：
Tan, Zengqi
中科院分区：
文献类型：
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作者：
Cheng, Lanming;Cao, Lin;Tan, Zengqi
糖基化是蛋白质翻译后最普遍和最多样化的修饰，在许多生理和病理事件中起着至关重要的生物学作用。n -聚糖的改变在乳腺癌进展过程中被检测到。在特定的n -聚糖结构中，分切n -乙酰氨基葡萄糖（GlcNAc）是一种连接在核心β-甘露糖残基上的β1,4链GlcNAc，由糖基转移酶MGAT3催化。平分GlcNAc水平在不同类型的癌症中普遍失调。在这项研究中，我们利用质谱和凝集素微阵列分析来研究乳腺癌细胞中异常的n -聚糖。我们的数据显示，与正常上皮细胞相比，乳腺癌细胞中分割GlcNAc水平降低，MGAT3表达下调。利用植物凝集素PHA-E（一种识别并结合分割GlcNAc的植物凝集素）富集技术，结合nanoLC-MS/MS对不同乳腺癌细胞中含有分割GlcNAc的糖蛋白进行了分析。在差异表达的糖蛋白中，经免疫染色和免疫沉淀证实，乳腺癌细胞中EGFR上的二分GlcNAc水平明显降低。我们在乳腺癌MDA-MB-231细胞中过表达MGAT3，过表达MGAT3可显著增强EGFR的分割N-GlcNAc，抑制EGFR/Erk信号，从而导致细胞迁移能力、细胞增殖和克隆形成降低。综上所述，我们得出结论，在EGFR上分割N-GlcNAc通过下调EGFR/Erk信号抑制乳腺癌的恶性表型。
Glycosylation, the most prevalent and diverse post-translational modification of protein, plays crucial biological roles in many physiological and pathological events. Alteration of N-glycan has been detected during breast cancer progression. Among the specific N-glycan structures, bisecting N-Acetylglucosamine (GlcNAc) is a β1,4-linked GlcNAc attached to the core β-mannose residue, and is catalyzed by glycosyltransferase MGAT3. Bisecting GlcNAc levels were commonly dysregulated in different types of cancer. In this study, we utilized mass spectrometry and lectin microarray analysis to investigate aberrant N-glycans in breast cancer cells. Our data showed the decreased levels of bisecting GlcNAc and down-regulated expression of MGAT3 in breast cancer cells than normal epithelial cells. Using PHA-E (a plant lectin recognizing and combining bisecting GlcNAc) based enrichment coupled with nanoLC-MS/MS, we analyzed the glycoproteins bearing bisecting GlcNAc in various breast cancer cells. Among the differentially expressed glycoproteins, levels of bisecting GlcNAc on EGFR were significantly decreased in breast cancer cells, confirmed by immunostaining and immunoprecipitation. We overexpressed MGAT3 in breast cancer MDA-MB-231 cells, and overexpression of MGAT3 significantly enhanced the bisecting N-GlcNAc on EGFR and suppressed the EGFR/Erk signaling, which further resulted in the reduction of migratory ability, cell proliferation, and clonal formation. Taken together, we conclude that bisecting N-GlcNAc on EGFR inhibits malignant phenotype of breast cancer via down-regulation of EGFR/Erk signaling.