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Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis

FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(...

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Autores principales: Duan, Shanshan, Moro, Loredana, Qu, Rui, Simoneschi, Daniele, Cho, Hyunwoo, Jiang, Shaowen, Zhao, Huiyong, Chang, Qing, de Stanchina, Elisa, Arbini, Arnaldo A., Pagano, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577224/
https://www.ncbi.nlm.nih.gov/pubmed/34686346
http://dx.doi.org/10.1016/j.celrep.2021.109870
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author Duan, Shanshan
Moro, Loredana
Qu, Rui
Simoneschi, Daniele
Cho, Hyunwoo
Jiang, Shaowen
Zhao, Huiyong
Chang, Qing
de Stanchina, Elisa
Arbini, Arnaldo A.
Pagano, Michele
author_facet Duan, Shanshan
Moro, Loredana
Qu, Rui
Simoneschi, Daniele
Cho, Hyunwoo
Jiang, Shaowen
Zhao, Huiyong
Chang, Qing
de Stanchina, Elisa
Arbini, Arnaldo A.
Pagano, Michele
author_sort Duan, Shanshan
collection PubMed
description FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(FBXO31) promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and −2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer.
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spelling pubmed-85772242021-11-09 Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis Duan, Shanshan Moro, Loredana Qu, Rui Simoneschi, Daniele Cho, Hyunwoo Jiang, Shaowen Zhao, Huiyong Chang, Qing de Stanchina, Elisa Arbini, Arnaldo A. Pagano, Michele Cell Rep Article FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1(FBXO31) promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and −2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer. 2021-10-19 /pmc/articles/PMC8577224/ /pubmed/34686346 http://dx.doi.org/10.1016/j.celrep.2021.109870 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Duan, Shanshan
Moro, Loredana
Qu, Rui
Simoneschi, Daniele
Cho, Hyunwoo
Jiang, Shaowen
Zhao, Huiyong
Chang, Qing
de Stanchina, Elisa
Arbini, Arnaldo A.
Pagano, Michele
Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title_full Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title_fullStr Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title_full_unstemmed Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title_short Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis
title_sort loss of fbxo31-mediated degradation of dusp6 dysregulates erk and pi3k-akt signaling and promotes prostate tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577224/
https://www.ncbi.nlm.nih.gov/pubmed/34686346
http://dx.doi.org/10.1016/j.celrep.2021.109870
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