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A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma

SIMPLE SUMMARY: Group 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a poor prognosis. FBXW7, a critical tumor suppressor in many types of cancer, regulates the proteasome-mediated degradation of oncoproteins including MYC. However, the role of FBXW7 in the tumorigenesis of...

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Autores principales: Wang, Dong, Pierce, Angela, Veo, Bethany, Fosmire, Susan, Danis, Etienne, Donson, Andrew, Venkataraman, Sujatha, Vibhakar, Rajeev
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865656/
https://www.ncbi.nlm.nih.gov/pubmed/33494392
http://dx.doi.org/10.3390/cancers13030387
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author Wang, Dong
Pierce, Angela
Veo, Bethany
Fosmire, Susan
Danis, Etienne
Donson, Andrew
Venkataraman, Sujatha
Vibhakar, Rajeev
author_facet Wang, Dong
Pierce, Angela
Veo, Bethany
Fosmire, Susan
Danis, Etienne
Donson, Andrew
Venkataraman, Sujatha
Vibhakar, Rajeev
author_sort Wang, Dong
collection PubMed
description SIMPLE SUMMARY: Group 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a poor prognosis. FBXW7, a critical tumor suppressor in many types of cancer, regulates the proteasome-mediated degradation of oncoproteins including MYC. However, the role of FBXW7 in the tumorigenesis of group 3 MB has not been well studied. In this study, we show that FBXW7 is downregulated in group 3 MB patient samples, and FBXW7 stabilization is crucial for inhibiting c-MYC. We identified a FBXW7-MYC-PLK1 regulatory loop in MYC-driven MB, which provides a mechanism of using protein kinase inhibitors for translation in the future. ABSTRACT: Polo-like kinase 1 (PLK1) is highly expressed in group 3 medulloblastoma (MB), and it has been preclinically validated as a cancer therapeutic target in medulloblastoma. Here, we demonstrate that PLK1 inhibition with PCM-075 or BI6727 significantly reduces the growth of MB cells and causes a decrease of c-MYC mRNA and protein levels. We show that MYC activates PLK1 transcription, while the inhibition of PLK1 suppresses MB tumor development and causes a decrease in c-MYC protein level by suppressing FBXW7 auto poly-ubiquitination. FBXW7 physically interacts with PLK1 and c-MYC, facilitating their protein degradation by promoting ubiquitination. These results demonstrate a PLK1-FBXW7-MYC regulatory loop in MYC-driven medulloblastoma. Moreover, FBXW7 is significantly downregulated in group 3 patient samples. The overexpression of FBXW7 induced apoptosis and suppressed proliferation in vitro and in vivo, while constitutive phosphorylation mutation attenuated its tumor suppressor function. Altogether, these findings demonstrated that PLK1 inhibition stabilizes FBXW7 in MYC-driven MB, thus revealing an important function of FBXW7 in suppressing medulloblastoma progression.
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spelling pubmed-78656562021-02-07 A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma Wang, Dong Pierce, Angela Veo, Bethany Fosmire, Susan Danis, Etienne Donson, Andrew Venkataraman, Sujatha Vibhakar, Rajeev Cancers (Basel) Article SIMPLE SUMMARY: Group 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a poor prognosis. FBXW7, a critical tumor suppressor in many types of cancer, regulates the proteasome-mediated degradation of oncoproteins including MYC. However, the role of FBXW7 in the tumorigenesis of group 3 MB has not been well studied. In this study, we show that FBXW7 is downregulated in group 3 MB patient samples, and FBXW7 stabilization is crucial for inhibiting c-MYC. We identified a FBXW7-MYC-PLK1 regulatory loop in MYC-driven MB, which provides a mechanism of using protein kinase inhibitors for translation in the future. ABSTRACT: Polo-like kinase 1 (PLK1) is highly expressed in group 3 medulloblastoma (MB), and it has been preclinically validated as a cancer therapeutic target in medulloblastoma. Here, we demonstrate that PLK1 inhibition with PCM-075 or BI6727 significantly reduces the growth of MB cells and causes a decrease of c-MYC mRNA and protein levels. We show that MYC activates PLK1 transcription, while the inhibition of PLK1 suppresses MB tumor development and causes a decrease in c-MYC protein level by suppressing FBXW7 auto poly-ubiquitination. FBXW7 physically interacts with PLK1 and c-MYC, facilitating their protein degradation by promoting ubiquitination. These results demonstrate a PLK1-FBXW7-MYC regulatory loop in MYC-driven medulloblastoma. Moreover, FBXW7 is significantly downregulated in group 3 patient samples. The overexpression of FBXW7 induced apoptosis and suppressed proliferation in vitro and in vivo, while constitutive phosphorylation mutation attenuated its tumor suppressor function. Altogether, these findings demonstrated that PLK1 inhibition stabilizes FBXW7 in MYC-driven MB, thus revealing an important function of FBXW7 in suppressing medulloblastoma progression. MDPI 2021-01-21 /pmc/articles/PMC7865656/ /pubmed/33494392 http://dx.doi.org/10.3390/cancers13030387 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Dong
Pierce, Angela
Veo, Bethany
Fosmire, Susan
Danis, Etienne
Donson, Andrew
Venkataraman, Sujatha
Vibhakar, Rajeev
A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title_full A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title_fullStr A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title_full_unstemmed A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title_short A Regulatory Loop of FBXW7-MYC-PLK1 Controls Tumorigenesis of MYC-Driven Medulloblastoma
title_sort regulatory loop of fbxw7-myc-plk1 controls tumorigenesis of myc-driven medulloblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865656/
https://www.ncbi.nlm.nih.gov/pubmed/33494392
http://dx.doi.org/10.3390/cancers13030387
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