2. Academic Validation
  3. Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer

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

  • Cell Death Differ. 2020 Apr;27(4):1341-1354. doi: 10.1038/s41418-019-0419-1.
Soyeon Shin 1,  Kyungeun Kim 2 3,  Hwa-Ryeon Kim 1,  Kris Ylaya 2,  Sung-Im Do 3,  Stephen M Hewitt 2,  Hee-Sae Park 4,  Jae-Seok Roe 1,  Joon-Yong Chung 2,  Jaewhan Song 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
  • 2 Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 3 Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 03181, Republic of Korea.
  • 4 Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
  • 5 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea. jso678@yonsei.ac.kr.
PMID: 31527799 DOI: 10.1038/s41418-019-0419-1
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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