LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis via modulating GALNT1 activity
LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis via modulating GALNT1 activity
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LAMTOR5 通过调节 GALNT1 活性提高乳腺癌转移中 O-糖基化的异常起始
DOI：
10.1038/s41388-019-1146-2
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发表时间：
2020-03-01
期刊：
影响因子：
8
通讯作者：
Ye, Lihong
中科院分区：
文献类型：
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作者：
Fang, Runping;Xu, Feifei;Ye, Lihong
在恶性肿瘤期间，扰动的O-糖基化对癌症进展具有全局影响。作为肿瘤转移标志的GalNAc型O-糖基化起始异常升高，但其调控机制仍不清楚。在这里，我们表明LAMTOR 5在乳腺癌转移中引起O-糖基化的异常起始。LAMTOR 5在乳腺癌组织中高表达，并与Tn抗原（O-糖基化起始产物）相关。LAMTOR 5调节的O-糖基化起始酶GALNT 1赋予Tn积累并预测较差的存活率。在机制上，LAMTOR 5通过共激活c-Jun刺激GALNT 1的转录，并通过LAMTOR 5依赖性激活c-Src触发GALNT 1在内质网（ER）中的移位。这种不寻常的O-糖基化起始导致大量Tn修饰的糖蛋白，如MUC 1和OPN。总的来说，我们的研究结果表明，LAMTOR 5/c-Jun/c-Src轴作为异常O-糖基化起始的上游调节剂和潜在的治疗靶点在乳腺癌转移。
During malignancy, perturbed O-glycosylation confers global influence on cancer progression. As a hallmark of cancer metastasis, GalNAc-type O-glycosylation initiation is aberrantly raised, but the regulatory mechanism is still mysterious. Here, we show that LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis. LAMTOR5 was highly expressed in adenocarcinoma and correlated with Tn antigen, a product of O-glycosylation initiation, in both clinical metastatic breast cancer specimens and secondary metastasis mouse model. LAMTOR5-modulated O-glycosylation initiating enzyme GALNT1 conferred Tn accumulation and predicted poor survival. Mechanistically, LAMTOR5 stimulated transcriptions of GALNT1 through coactivating c-Jun, and triggered dislocation of GALNT1 in the endoplasmic reticulum (ER) via LAMTOR5 dependent-activation of c-Src. This unusual initiation of O-glycosylation resulted in the abundance of Tn modified glycoproteins, such as MUC1 and OPN. Collectively, our findings indicate that LAMTOR5/c-Jun/c-Src axis serves as the upstream regulator of abnormal O-glycosylation initiation and potential therapeutic targets in breast cancer metastasis.