FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression.
Cell Line, Tumor
Cell Proliferation
Deoxycytidine
/ analogs & derivatives
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition
/ genetics
Forkhead Box Protein M1
/ biosynthesis
Humans
Pancreatic Neoplasms
/ drug therapy
Signal Transduction
Ubiquitins
/ genetics
Gemcitabine
Pancreatic Neoplasms
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 05 2022
25 05 2022
Historique:
received:
14
11
2021
accepted:
17
05
2022
revised:
16
05
2022
entrez:
25
5
2022
pubmed:
26
5
2022
medline:
28
5
2022
Statut:
epublish
Résumé
Pancreatic cancer (PC) is one of the deadliest malignant tumors, and its resistance to gemcitabine chemotherapy is the primary reason for poor prognosis in patients. Ubiquitin-like protein FAT10 has recently been reported to promote tumor chemotherapy resistance. In this study, the expression of FAT10 in PC was significantly higher than that in adjacent noncancerous tissues. Increased expression of FAT10 in PC was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of FAT10 inhibits the proliferation and epithelial-mesenchymal transition (EMT) of PC cells, promotes the apoptosis of PC cells, and enhances sensitivity to gemcitabine chemotherapy. In addition, upregulation of FAT10 increased the expression of FOXM1 protein. The effect of downregulating FAT10 was reversed by FOXM1 overexpression, and FOXM1 knockdown inhibited EMT driven by FAT10 overexpression. Mechanistically, FAT10 stabilized the expression of FOXM1 by competing with ubiquitin to bind FOXM1 and inhibiting the ubiquitination-mediated degradation of FOXM1. In conclusion, the FAT10-FOXM1 axis is a pivotal driver of PC proliferation and gemcitabine resistance, and the results provide novel insights into chemotherapy resistance in PC.
Identifiants
pubmed: 35614040
doi: 10.1038/s41419-022-04960-0
pii: 10.1038/s41419-022-04960-0
pmc: PMC9132907
doi:
Substances chimiques
FOXM1 protein, human
0
Forkhead Box Protein M1
0
UBD protein, human
0
Ubiquitins
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
497Informations de copyright
© 2022. The Author(s).
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