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LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis via modulating GALNT1 activity

Oncogene volume 39, pages 2290–2304 (2020)Cite this article

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Abstract

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.

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Fig. 1: LAMTOR5 promotes abnormal initiation of O-glycosylation in breast cancer metastasis.
Fig. 2: LAMTOR5-elevated GALNT1 contributes to abnormal initiation of O-glycosylation and breast cancer cell invasion and migration.
Fig. 3: LAMTOR5 stimulates GALNT1 transcription through coactivating transcription factor c-Jun.
Fig. 4: LAMTOR5 triggers GALNT1/Tn antigen to localize in the ER via promoting expression and activation of c-Src.
Fig. 5: LAMTOR5 increases O-glycosylation initiation of MUC1 and OPN.
Fig. 6: LAMTOR5 promotes breast cancer metastasis through GALNT1-mediated abnormal initiation of O-glycosylation.

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Acknowledgements

This project was supported by the grants of the National Basic Research Program of China (973 Program nos. 2015CB553905, 2015CB553703), the National Natural Scientific Foundation of China (nos. 81372186, 31670771, 31470756, and 31670769), the Fundamental Research Funds for the Central Universities, Project of Prevention and Treatment of Key Infectious Diseases (no. 2014ZX0002002-005) and Project of Prevention and Control of Key Chronic Non Infectious Diseases (no. 2016YFC130340) to LHY.

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  1. State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Runping Fang, Feifei Xu, Hui Shi, Yue Wu, Can Cao, Hang Li, Kai Ye, Yingyi Zhang, Qian Liu, Shuqin Zhang, Weiying Zhang & Lihong Ye

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RPF, WYZ, and LHY designed research and wrote the paper; RPF, FFX, HS, YW, CC, HL, YYZ, and QL performed research; RPF, FFX, HS, YW, CC, WYZ, and LHY analyzed data.

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Fang, R., Xu, F., Shi, H. et al. LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis via modulating GALNT1 activity. Oncogene 39, 2290–2304 (2020). https://doi.org/10.1038/s41388-019-1146-2

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