Cargando…

Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

BACKGROUND: Hypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in th...

Descripción completa

Detalles Bibliográficos
Autores principales: Cao, Wenpeng, Zeng, Zhirui, Pan, Runsang, Wu, Hao, Zhang, Xiangyan, Chen, Hui, Nie, Yingjie, Yu, Zijiang, Lei, Shan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247946/
https://www.ncbi.nlm.nih.gov/pubmed/34221996
http://dx.doi.org/10.3389/fonc.2021.675991
_version_ 1783716619617304576
author Cao, Wenpeng
Zeng, Zhirui
Pan, Runsang
Wu, Hao
Zhang, Xiangyan
Chen, Hui
Nie, Yingjie
Yu, Zijiang
Lei, Shan
author_facet Cao, Wenpeng
Zeng, Zhirui
Pan, Runsang
Wu, Hao
Zhang, Xiangyan
Chen, Hui
Nie, Yingjie
Yu, Zijiang
Lei, Shan
author_sort Cao, Wenpeng
collection PubMed
description BACKGROUND: Hypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in the progression of PC. METHODS: In the preliminary study, bioinformatics analysis predicted FUT11 as a key hypoxia associated gene in PC. The expression of FUT11 in PC was evaluated using quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation and migration under normoxia and hypoxia were evaluated using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine (EDU) assay, colony formation assay and transwell assay. The effects of FUT11 in vivo was examined in mouse tumor models of liver metastasis and subcutaneous xenograft. Furthermore, Western blot, luciferase assay and immunoprecipitation were performed to explore the regulatory relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC. RESULTS: FUT11 was markedly increased of PC cells with hypoxia, upregulated in the PC clinical tissues, and predicted a poor outcome of PC patients. Inhibition of FUT11 reduced PC cell growth and migratory ability of PC cells under normoxia and hypoxia conditions in vitro, and growth and tumor cell metastasis in vivo. FUT11 bound to PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 interacted with PDK1 and decreased the ubiquitination of PDK1, lead to the activation of AKT/mTOR signaling pathway. FUT11 knockdown significantly increased the degradation of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressive impacts of FUT11 knockdown on PC cell growth and migration. In addition, HIF1α bound to the promoter of FUT11 and increased its expression, as well as co-expressed with FUT11 in PC tissues. Furthermore, overexpression of FUT11 partially rescued the suppressive effects of HIF1α knockdown on PC cell growth and migration in hypoxia condition. CONCLUSION: Our data implicate that hypoxia-induced FUT11 contributes to proliferation and metastasis of PC by maintaining the stability of PDK1, thus mediating activation of AKT/mTOR signaling pathway, and suggest that FUT11 could be a novel and effective target for the treatment of pancreatic cancer.
format Online
Article
Text
id pubmed-8247946
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-82479462021-07-02 Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1 Cao, Wenpeng Zeng, Zhirui Pan, Runsang Wu, Hao Zhang, Xiangyan Chen, Hui Nie, Yingjie Yu, Zijiang Lei, Shan Front Oncol Oncology BACKGROUND: Hypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in the progression of PC. METHODS: In the preliminary study, bioinformatics analysis predicted FUT11 as a key hypoxia associated gene in PC. The expression of FUT11 in PC was evaluated using quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation and migration under normoxia and hypoxia were evaluated using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine (EDU) assay, colony formation assay and transwell assay. The effects of FUT11 in vivo was examined in mouse tumor models of liver metastasis and subcutaneous xenograft. Furthermore, Western blot, luciferase assay and immunoprecipitation were performed to explore the regulatory relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC. RESULTS: FUT11 was markedly increased of PC cells with hypoxia, upregulated in the PC clinical tissues, and predicted a poor outcome of PC patients. Inhibition of FUT11 reduced PC cell growth and migratory ability of PC cells under normoxia and hypoxia conditions in vitro, and growth and tumor cell metastasis in vivo. FUT11 bound to PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 interacted with PDK1 and decreased the ubiquitination of PDK1, lead to the activation of AKT/mTOR signaling pathway. FUT11 knockdown significantly increased the degradation of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressive impacts of FUT11 knockdown on PC cell growth and migration. In addition, HIF1α bound to the promoter of FUT11 and increased its expression, as well as co-expressed with FUT11 in PC tissues. Furthermore, overexpression of FUT11 partially rescued the suppressive effects of HIF1α knockdown on PC cell growth and migration in hypoxia condition. CONCLUSION: Our data implicate that hypoxia-induced FUT11 contributes to proliferation and metastasis of PC by maintaining the stability of PDK1, thus mediating activation of AKT/mTOR signaling pathway, and suggest that FUT11 could be a novel and effective target for the treatment of pancreatic cancer. Frontiers Media S.A. 2021-06-17 /pmc/articles/PMC8247946/ /pubmed/34221996 http://dx.doi.org/10.3389/fonc.2021.675991 Text en Copyright © 2021 Cao, Zeng, Pan, Wu, Zhang, Chen, Nie, Yu and Lei https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Cao, Wenpeng
Zeng, Zhirui
Pan, Runsang
Wu, Hao
Zhang, Xiangyan
Chen, Hui
Nie, Yingjie
Yu, Zijiang
Lei, Shan
Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title_full Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title_fullStr Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title_full_unstemmed Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title_short Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1
title_sort hypoxia-related gene fut11 promotes pancreatic cancer progression by maintaining the stability of pdk1
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247946/
https://www.ncbi.nlm.nih.gov/pubmed/34221996
http://dx.doi.org/10.3389/fonc.2021.675991
work_keys_str_mv AT caowenpeng hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT zengzhirui hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT panrunsang hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT wuhao hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT zhangxiangyan hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT chenhui hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT nieyingjie hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT yuzijiang hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1
AT leishan hypoxiarelatedgenefut11promotespancreaticcancerprogressionbymaintainingthestabilityofpdk1