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FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression

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 FAT...

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Autores principales: Zhu, Jinfeng, Zhao, Jiefeng, Luo, Chen, Zhu, Zhengming, Peng, Xingyu, Zhu, Xiaojian, Lin, Kang, Bu, Fanqin, Zhang, Wenjun, Li, Qing, Wang, Kai, Hu, Zhigang, Yu, Xin, Chen, Leifeng, Yuan, Rongfa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132907/
https://www.ncbi.nlm.nih.gov/pubmed/35614040
http://dx.doi.org/10.1038/s41419-022-04960-0
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author Zhu, Jinfeng
Zhao, Jiefeng
Luo, Chen
Zhu, Zhengming
Peng, Xingyu
Zhu, Xiaojian
Lin, Kang
Bu, Fanqin
Zhang, Wenjun
Li, Qing
Wang, Kai
Hu, Zhigang
Yu, Xin
Chen, Leifeng
Yuan, Rongfa
author_facet Zhu, Jinfeng
Zhao, Jiefeng
Luo, Chen
Zhu, Zhengming
Peng, Xingyu
Zhu, Xiaojian
Lin, Kang
Bu, Fanqin
Zhang, Wenjun
Li, Qing
Wang, Kai
Hu, Zhigang
Yu, Xin
Chen, Leifeng
Yuan, Rongfa
author_sort Zhu, Jinfeng
collection PubMed
description 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.
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spelling pubmed-91329072022-05-27 FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression Zhu, Jinfeng Zhao, Jiefeng Luo, Chen Zhu, Zhengming Peng, Xingyu Zhu, Xiaojian Lin, Kang Bu, Fanqin Zhang, Wenjun Li, Qing Wang, Kai Hu, Zhigang Yu, Xin Chen, Leifeng Yuan, Rongfa Cell Death Dis Article 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. Nature Publishing Group UK 2022-05-25 /pmc/articles/PMC9132907/ /pubmed/35614040 http://dx.doi.org/10.1038/s41419-022-04960-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhu, Jinfeng
Zhao, Jiefeng
Luo, Chen
Zhu, Zhengming
Peng, Xingyu
Zhu, Xiaojian
Lin, Kang
Bu, Fanqin
Zhang, Wenjun
Li, Qing
Wang, Kai
Hu, Zhigang
Yu, Xin
Chen, Leifeng
Yuan, Rongfa
FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title_full FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title_fullStr FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title_full_unstemmed FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title_short FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression
title_sort fat10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of foxm1 expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132907/
https://www.ncbi.nlm.nih.gov/pubmed/35614040
http://dx.doi.org/10.1038/s41419-022-04960-0
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