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

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 deubiquit...

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Bibliographic Details
Published in:Cell death and differentiation 2020-04, Vol.27 (4), p.1341-1354
Main Authors: Shin, Soyeon, Kim, Kyungeun, Kim, Hwa-Ryeon, Ylaya, Kris, Do, Sung-Im, Hewitt, Stephen M., Park, Hee-Sae, Roe, Jae-Seok, Chung, Joon-Yong, Song, Jaewhan
Format: Article
Language:English
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Apoptosis
Biochemistry
Biomedical and Life Sciences
Breast cancer
Cell Biology
Cell Cycle Analysis
Intracellular
Life Sciences
Notch1 protein
Signal transduction
Stem Cells
Therapeutic applications
Therapeutic targets
Tumor cell lines
Tumorigenesis
Ubiquitin
Ubiquitin-specific proteinase
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-019-0419-1