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Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis

Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion pr...

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Autores principales: Niu, Mengmeng, He, Yajun, Xu, Jing, Ding, Liangping, He, Tao, Yi, Yong, Fu, Mengyuan, Guo, Rongtian, Li, Fengtian, Chen, Hu, Chen, Ye-Guang, Xiao, Zhi-Xiong Jim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939357/
https://www.ncbi.nlm.nih.gov/pubmed/33626035
http://dx.doi.org/10.1371/journal.pbio.3001113
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author Niu, Mengmeng
He, Yajun
Xu, Jing
Ding, Liangping
He, Tao
Yi, Yong
Fu, Mengyuan
Guo, Rongtian
Li, Fengtian
Chen, Hu
Chen, Ye-Guang
Xiao, Zhi-Xiong Jim
author_facet Niu, Mengmeng
He, Yajun
Xu, Jing
Ding, Liangping
He, Tao
Yi, Yong
Fu, Mengyuan
Guo, Rongtian
Li, Fengtian
Chen, Hu
Chen, Ye-Guang
Xiao, Zhi-Xiong Jim
author_sort Niu, Mengmeng
collection PubMed
description Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-β receptor I (TβRI), FBXO3, and p63 protein expression and that high expression of TβRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-β signaling in promoting tumor metastasis and that the TβRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment.
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spelling pubmed-79393572021-03-18 Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis Niu, Mengmeng He, Yajun Xu, Jing Ding, Liangping He, Tao Yi, Yong Fu, Mengyuan Guo, Rongtian Li, Fengtian Chen, Hu Chen, Ye-Guang Xiao, Zhi-Xiong Jim PLoS Biol Research Article Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-independent but Erk-dependent manner. Knockdown of FBXO3 or restoration of ΔNp63α expression effectively rescues TGF-β-induced EMT, cell motility, and tumor metastasis in vitro and in vivo. Furthermore, clinical analyses reveal a significant correlation among TGF-β receptor I (TβRI), FBXO3, and p63 protein expression and that high expression of TβRI/FBXO3 and low expression of p63 are associated with poor recurrence-free survival (RFS). Together, these results demonstrate that FBXO3 facilitates ΔNp63α degradation to empower TGF-β signaling in promoting tumor metastasis and that the TβRI-FBXO3-ΔNp63α axis is critically important in breast cancer development and clinical prognosis. This study suggests that FBXO3 may be a potential therapeutic target for advanced breast cancer treatment. Public Library of Science 2021-02-24 /pmc/articles/PMC7939357/ /pubmed/33626035 http://dx.doi.org/10.1371/journal.pbio.3001113 Text en © 2021 Niu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Niu, Mengmeng
He, Yajun
Xu, Jing
Ding, Liangping
He, Tao
Yi, Yong
Fu, Mengyuan
Guo, Rongtian
Li, Fengtian
Chen, Hu
Chen, Ye-Guang
Xiao, Zhi-Xiong Jim
Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title_full Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title_fullStr Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title_full_unstemmed Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title_short Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis
title_sort noncanonical tgf-β signaling leads to fbxo3-mediated degradation of δnp63α promoting breast cancer metastasis and poor clinical prognosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939357/
https://www.ncbi.nlm.nih.gov/pubmed/33626035
http://dx.doi.org/10.1371/journal.pbio.3001113
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