USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
13 Mar 2021
13 Mar 2021
Historique:
received:
28
10
2020
accepted:
10
02
2021
revised:
08
02
2021
entrez:
14
3
2021
pubmed:
15
3
2021
medline:
15
3
2021
Statut:
epublish
Résumé
Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.
Identifiants
pubmed: 33714979
doi: 10.1038/s41389-021-00318-x
pii: 10.1038/s41389-021-00318-x
pmc: PMC7956144
doi:
Types de publication
Journal Article
Langues
eng
Pagination
28Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : P30CA046934
Organisme : NIGMS NIH HHS
ID : R01 GM120109
Pays : United States
Organisme : Ministry of Science, Technology and Productive Innovation, Argentina | Agencia Nacional de Promoción Científica y Tecnológica (National Agency for Science and Technology, Argentina)
ID : PICT 2016-2620
Organisme : NCI NIH HHS
ID : R01 CA117907
Pays : United States
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01CA117907
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : id18467
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : Ministry of Science, Technology and Productive Innovation, Argentina | Agencia Nacional de Promoción Científica y Tecnológica (National Agency for Science and Technology, Argentina)
ID : PICT 2011-2783
Organisme : Ministry of Science, Technology and Productive Innovation, Argentina | Agencia Nacional de Promoción Científica y Tecnológica (National Agency for Science and Technology, Argentina)
ID : PICT 2018-03688
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01GM120109
Organisme : National Science Foundation (NSF)
ID : MCB-1817582
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