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Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity

Oncogene volume 36, pages 6391–6407 (2017)Cite this article

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Abstract

The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal–epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial–mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT–MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.

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Acknowledgements

This work was supported by the following awards: 81500410 (to YT), 81170340 and 81372557 (to RW) from the National Natural Science Foundation of China.

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Authors and Affiliations

  1. Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China

    J Ye, X Wei, Y Shang, Q Pan, M Yang, Y Tian, Y He, Z Peng, L Chen, W Chen & R Wang

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Ye, J., Wei, X., Shang, Y. et al. Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity. Oncogene 36, 6391–6407 (2017). https://doi.org/10.1038/onc.2017.241

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