Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer

Abstract

Notch, an essential factor in tissue development and homoeostasis, has been reported to play an oncogenic function in a variety of cancers. Here, we report ubiquitin-specific protease 8 (USP8) as a novel deubiquitylase of Notch1 intracellular domain (NICD). USP8 specifically stabilizes and deubiquitylates NICD through a direct interaction. The inhibition of USP8 downregulated the Notch signalling pathway via NICD destabilization, resulting in the retardation of cellular growth, wound closure, and colony forming ability of breast cancer cell lines. These phenomena were restored by the reconstitution of NICD or USP8, supporting the direct interaction between these two proteins. The expression levels of NICD and USP8 proteins were positively correlated in patients with advanced breast cancer. Taken together, our results suggest that USP8 functions as a positive regulator of Notch signalling, offering a therapeutic target for breast cancer.

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Acknowledgements

This research was supported by grants from the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) (JS). In addition, this research was partially supported by the BK21 Plus project of the National Research Foundation of Korea Grant.

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Shin, S., Kim, K., Kim, HR. et al. Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer. Cell Death Differ 27, 1341–1354 (2020). https://doi.org/10.1038/s41418-019-0419-1

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