Research Paper Volume 12, Issue 19 pp 19273—19292
Deubiquitinase USP18 promotes the progression of pancreatic cancer via enhancing the Notch1-c-Myc axis
- 1 Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, China
- 2 Hepatopancreatobiliary Surgery Division, Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, China
- 3 Department of General Surgery, Hunan Youxian People's Hospital, Youxian, China
- 4 The Second Clinical Medical College, Nanchang University, Nanchang, China
Received: April 16, 2020 Accepted: July 6, 2020 Published: October 13, 2020https://doi.org/10.18632/aging.103760
How to Cite
Copyright: © 2020 Feng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of most cellular proteins, has been implicated in many human diseases, including cancers. Thus, DUBs can be considered potential therapeutic targets for many cancers. However, the role of deubiquitinase ubiquitin-specific protease 18 (USP18) in pancreatic cancer remains unknown. Here, we found that the deubiquitinase ubiquitin-specific protease 18 (USP18) is significantly upregulated in pancreatic cancer and is correlated with a shorter median overall and relapse-free survival. A functional assay demonstrated that overexpression of USP18 resulted in increased proliferation of pancreatic cancer cells. Conversely, these phenomena were reversed after USP18 was silenced in pancreatic cancer cells. Further investigation revealed that USP18 promoted cell progression by increasing c-Myc expression, which has been reported to control pancreatic cancer progression, and our data demonstrated that c-Myc is key for USP18-mediated pancreatic cancer cell progression in vitro and in vivo. Moreover, we found that USP18 promoted pancreatic cancer progression via upregulation of Notch-1-dependent c-Myc. Mechanistically, USP18 interacts with and removes K48-linked ubiquitin chains from Notch1, thereby stabilizing Notch1 and promoting the Notch1-c-Myc pathway. Our work identifies and validates USP18 as a pancreatic cancer oncogene and provides a potential druggable target for this intractable disease.
DUBs: deubiquitinating enzymes; USP18: deubiquitinase ubiquitin-specific protease 18; ISG15: interferon (IFN)-stimulated gene 15; CHX: cycloheximide; TCGA: The Cancer Genome Atlas; GBM: Glioblastoma multiforme; IHC: Immunohistochemistry; IF: Immunofluorescence; Co-IP: Co-immunoprecipitation.