MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma

Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; t...

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Autores principales:	Sarah E. Woodfield, Yan Shi, Roma H. Patel, Zhenghu Chen, Aayushi P. Shah, Richard S. Whitlock, Aryana M. Ibarra, Samuel R. Larson, Stephen F. Sarabia, Andrew Badachhape, Zbigniew Starosolski, Ketan B. Ghaghada, Pavel Sumazin, D. Allen Annis, Dolores López-Terrada, Sanjeev A. Vasudevan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c835b5e701047a99457ad48818f16a6
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spelling	oai:doaj.org-article:2c835b5e701047a99457ad48818f16a62021-12-02T10:44:14ZMDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma10.1038/s41598-021-82542-42045-2322https://doaj.org/article/2c835b5e701047a99457ad48818f16a62021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82542-4https://doaj.org/toc/2045-2322Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.Sarah E. WoodfieldYan ShiRoma H. PatelZhenghu ChenAayushi P. ShahRichard S. WhitlockAryana M. IbarraSamuel R. LarsonStephen F. SarabiaAndrew BadachhapeZbigniew StarosolskiKetan B. GhaghadaPavel SumazinD. Allen AnnisDolores López-TerradaSanjeev A. VasudevanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sarah E. Woodfield Yan Shi Roma H. Patel Zhenghu Chen Aayushi P. Shah Richard S. Whitlock Aryana M. Ibarra Samuel R. Larson Stephen F. Sarabia Andrew Badachhape Zbigniew Starosolski Ketan B. Ghaghada Pavel Sumazin D. Allen Annis Dolores López-Terrada Sanjeev A. Vasudevan MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
description	Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.
format	article
author	Sarah E. Woodfield Yan Shi Roma H. Patel Zhenghu Chen Aayushi P. Shah Richard S. Whitlock Aryana M. Ibarra Samuel R. Larson Stephen F. Sarabia Andrew Badachhape Zbigniew Starosolski Ketan B. Ghaghada Pavel Sumazin D. Allen Annis Dolores López-Terrada Sanjeev A. Vasudevan
author_facet	Sarah E. Woodfield Yan Shi Roma H. Patel Zhenghu Chen Aayushi P. Shah Richard S. Whitlock Aryana M. Ibarra Samuel R. Larson Stephen F. Sarabia Andrew Badachhape Zbigniew Starosolski Ketan B. Ghaghada Pavel Sumazin D. Allen Annis Dolores López-Terrada Sanjeev A. Vasudevan
author_sort	Sarah E. Woodfield
title	MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
title_short	MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
title_full	MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
title_fullStr	MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
title_full_unstemmed	MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
title_sort	mdm4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2c835b5e701047a99457ad48818f16a6
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MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma

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