USP10 Regulates ZEB1 Ubiquitination and Protein Stability to Inhibit ZEB1-Mediated Colorectal Cancer Metastasis.
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
received:
11
07
2022
revised:
22
12
2022
accepted:
17
03
2023
medline:
2
6
2023
pubmed:
21
3
2023
entrez:
20
3
2023
Statut:
ppublish
Résumé
Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcription factor that can promote tumor invasion and metastasis by inducing epithelial-to-mesenchymal transition (EMT). To date, regulation of ZEB1 by RAS/RAF signaling remains unclear, and few studies have examined posttranslation modification of ZEB1, including its ubiquitination. In human colorectal cancer cell lines with RAS/RAF/MEK/ERK activation, an interaction of ZEB1 with the deubiquitinase ubiquitin-specific protease 10 (USP10) was identified whereby USP10 modifies ZEB1 ubiquitination and promotes its proteasomal degradation. Regulation of the USP10-ZEB1 interaction by MEK-ERK signaling was shown whereby constitutive activation of ERK can phosphorylate USP10 at Ser236 to impair its interaction with ZEB1 and enable ZEB1 protein stabilization. Stabilized ZEB1 was shown to promote colorectal cancer metastatic colonization in a mouse tail vein injection model. Conversely, MEK-ERK inhibition blocked USP10 phosphorylation and enhanced the USP10-ZEB1 interaction shown to suppress ZEB1-mediated tumor cell migration and metastasis. In conclusion, we demonstrate a novel function of USP10 in the regulation of ZEB1 protein stability and its ability to mediate tumor metastasis in a preclinical model. The MEK-ERK-regulated interaction of USP10 with ZEB1 can promote the proteasomal degradation of ZEB1 and thereby suppress its demonstrated ability to mediate tumor metastasis.
Identifiants
pubmed: 36940483
pii: 718834
doi: 10.1158/1541-7786.MCR-22-0552
pmc: PMC10239320
mid: NIHMS1886784
doi:
Substances chimiques
Zinc Finger E-box-Binding Homeobox 1
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
ZEB1 protein, human
0
USP10 protein, human
0
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
578-590Subventions
Organisme : NCI NIH HHS
ID : R01 CA210509
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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