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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-82542-4 |
| _version_ | 1818429264218816512 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T15:14:45Z |
| format | Article |
| id | doaj.art-2c835b5e701047a99457ad48818f16a6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:14:45Z |
| publishDate | 2021-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2c835b5e701047a99457ad48818f16a62022-12-21T22:56:24ZengNature PortfolioScientific Reports2045-23222021-02-0111111710.1038/s41598-021-82542-4MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastomaSarah E. Woodfield0Yan Shi1Roma H. Patel2Zhenghu Chen3Aayushi P. Shah4Richard S. Whitlock5Aryana M. Ibarra6Samuel R. Larson7Stephen F. Sarabia8Andrew Badachhape9Zbigniew Starosolski10Ketan B. Ghaghada11Pavel Sumazin12D. Allen Annis13Dolores López-Terrada14Sanjeev A. Vasudevan15Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalDepartment of Pathology and Immunology, Baylor College of Medicine, Molecular Oncology Laboratory, Texas Children’s HospitalSingleton Department of Pediatric Radiology, Texas Children’s HospitalSingleton Department of Pediatric Radiology, Texas Children’s HospitalSingleton Department of Pediatric Radiology, Texas Children’s HospitalDepartment of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of MedicineAileron Therapeutics IncDepartment of Pathology and Immunology, Baylor College of Medicine, Molecular Oncology Laboratory, Texas Children’s HospitalDivisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Texas Children’s HospitalAbstract 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.https://doi.org/10.1038/s41598-021-82542-4 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma |
| title_sort | mdm4 inhibition a novel therapeutic strategy to reactivate p53 in hepatoblastoma |
| url | https://doi.org/10.1038/s41598-021-82542-4 |
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