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LAMTOR5 raises abnormal initiation of O -glycosylation in breast cancer metastasis via modulating GALNT1 activity
Oncogene ( IF 6.9 ) Pub Date : 2019-12-13 , DOI: 10.1038/s41388-019-1146-2
Runping Fang 1 , Feifei Xu 1 , Hui Shi 1 , Yue Wu 1 , Can Cao 1 , Hang Li 1 , Kai Ye 1 , Yingyi Zhang 1 , Qian Liu 1 , Shuqin Zhang 1 , Weiying Zhang 1 , Lihong Ye 1
Affiliation  

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.



中文翻译:


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



在恶性肿瘤过程中, O-糖基化的紊乱对癌症进展产生全局影响。作为癌症转移的标志,GalNAc-型O-糖基化起始异常升高,但其调节机制仍然是个谜。在这里,我们发现 LAMTOR5 在乳腺癌转移中引发异常的O-糖基化起始。在临床转移性乳腺癌标本和继发性转移小鼠模型中,LAMTOR5 在腺癌中高表达,并与O-糖基化起始产物 Tn 抗原相关。 LAMTOR5 调节的O糖基化起始酶 GALNT1 导致 Tn 积累并预测较差的存活率。从机制上讲,LAMTOR5 通过共激活 c-Jun 刺激 GALNT1 转录,并通过 LAMTOR5 依赖性激活 c-Src 引发内质网 (ER) 中 GALNT1 的错位。这种不寻常的O-糖基化起始导致大量 Tn 修饰的糖蛋白,例如 MUC1 和 OPN。总的来说,我们的研究结果表明 LAMTOR5/c-Jun/c-Src 轴是异常O-糖基化起始的上游调节因子和乳腺癌转移的潜在治疗靶点。

更新日期:2019-12-17
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