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FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation

FBXW2 is a poorly characterized F-box protein, as a tumor suppressor that inhibits growth and metastasis of lung cancer by promoting ubiquitylation and degradation of oncogenic proteins, including SKP2 and β-catenin. However, what the biological functions of FBXW2 in prostate cancer cells and whethe...

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Autores principales: Zhou, Tao, Chen, Tingting, Lai, Bin, Zhang, Wenfeng, Luo, Xi, Xia, Ding, Fu, Weihua, Xu, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9061686/
https://www.ncbi.nlm.nih.gov/pubmed/35499593
http://dx.doi.org/10.1007/s00018-022-04320-3
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author Zhou, Tao
Chen, Tingting
Lai, Bin
Zhang, Wenfeng
Luo, Xi
Xia, Ding
Fu, Weihua
Xu, Jie
author_facet Zhou, Tao
Chen, Tingting
Lai, Bin
Zhang, Wenfeng
Luo, Xi
Xia, Ding
Fu, Weihua
Xu, Jie
author_sort Zhou, Tao
collection PubMed
description FBXW2 is a poorly characterized F-box protein, as a tumor suppressor that inhibits growth and metastasis of lung cancer by promoting ubiquitylation and degradation of oncogenic proteins, including SKP2 and β-catenin. However, what the biological functions of FBXW2 in prostate cancer cells and whether FBXW2 targets other substrates to involve in progression of prostate cancer is still unclear. Here, we reported that overexpression of FBXW2 attenuated proliferation and metastasis of PCa models both in vitro and in vivo, while FBXW2 depletion exhibited the opposite effects. Intriguingly, FBXW2 was an E3 ligase for EGFR in prostate cancer. EGFR protein level and its half-life were extended by FBXW2 depletion, while EGFR protein level was decreased, and its half-life was shortened upon overexpression of FBXW2, but not its dominant-negative mutant. Importantly, FBXW2 bond to EGFR via its consensus degron motif (TSNNST), and ubiquitylated and degraded EGFR, resulting in repression of EGF function. Thus, our data uncover a novel that FBXW2 as a tumor suppressor of prostate cancer, inhibits EGFR downstream by promoting EGFR ubiquitination and degradation, resulting in repression of cell proliferation and metastasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04320-3.
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spelling pubmed-90616862022-05-07 FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation Zhou, Tao Chen, Tingting Lai, Bin Zhang, Wenfeng Luo, Xi Xia, Ding Fu, Weihua Xu, Jie Cell Mol Life Sci Original Article FBXW2 is a poorly characterized F-box protein, as a tumor suppressor that inhibits growth and metastasis of lung cancer by promoting ubiquitylation and degradation of oncogenic proteins, including SKP2 and β-catenin. However, what the biological functions of FBXW2 in prostate cancer cells and whether FBXW2 targets other substrates to involve in progression of prostate cancer is still unclear. Here, we reported that overexpression of FBXW2 attenuated proliferation and metastasis of PCa models both in vitro and in vivo, while FBXW2 depletion exhibited the opposite effects. Intriguingly, FBXW2 was an E3 ligase for EGFR in prostate cancer. EGFR protein level and its half-life were extended by FBXW2 depletion, while EGFR protein level was decreased, and its half-life was shortened upon overexpression of FBXW2, but not its dominant-negative mutant. Importantly, FBXW2 bond to EGFR via its consensus degron motif (TSNNST), and ubiquitylated and degraded EGFR, resulting in repression of EGF function. Thus, our data uncover a novel that FBXW2 as a tumor suppressor of prostate cancer, inhibits EGFR downstream by promoting EGFR ubiquitination and degradation, resulting in repression of cell proliferation and metastasis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04320-3. Springer International Publishing 2022-05-02 2022 /pmc/articles/PMC9061686/ /pubmed/35499593 http://dx.doi.org/10.1007/s00018-022-04320-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Zhou, Tao
Chen, Tingting
Lai, Bin
Zhang, Wenfeng
Luo, Xi
Xia, Ding
Fu, Weihua
Xu, Jie
FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title_full FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title_fullStr FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title_full_unstemmed FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title_short FBXW2 inhibits prostate cancer proliferation and metastasis via promoting EGFR ubiquitylation and degradation
title_sort fbxw2 inhibits prostate cancer proliferation and metastasis via promoting egfr ubiquitylation and degradation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9061686/
https://www.ncbi.nlm.nih.gov/pubmed/35499593
http://dx.doi.org/10.1007/s00018-022-04320-3
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