Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth
Abstract Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06167-3 |
| _version_ | 1827802830582317056 |
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| author | Rosa Della Monica Michela Buonaiuto Mariella Cuomo Cristina Pagano Federica Trio Davide Costabile Giulia de Riso Francesca Sveva Cicala Maddalena Raia Raduan Ahmed Franca Marialaura Del Basso De Caro Domenico Sorrentino Giovanna Navarra Laura Coppola Lorella Tripodi Lucio Pastore Juergen Hench Stephan Frank Claudio Schonauer Giuseppe Catapano Maurizio Bifulco Lorenzo Chiariotti Roberta Visconti |
| author_facet | Rosa Della Monica Michela Buonaiuto Mariella Cuomo Cristina Pagano Federica Trio Davide Costabile Giulia de Riso Francesca Sveva Cicala Maddalena Raia Raduan Ahmed Franca Marialaura Del Basso De Caro Domenico Sorrentino Giovanna Navarra Laura Coppola Lorella Tripodi Lucio Pastore Juergen Hench Stephan Frank Claudio Schonauer Giuseppe Catapano Maurizio Bifulco Lorenzo Chiariotti Roberta Visconti |
| author_sort | Rosa Della Monica |
| collection | DOAJ |
| description | Abstract Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment. |
| first_indexed | 2024-03-11T20:45:39Z |
| format | Article |
| id | doaj.art-b44f13ef57b24faa81bbd847d68a87ec |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T20:45:39Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-b44f13ef57b24faa81bbd847d68a87ec2023-10-01T11:28:36ZengNature Publishing GroupCell Death and Disease2041-48892023-09-0114911310.1038/s41419-023-06167-3Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growthRosa Della Monica0Michela Buonaiuto1Mariella Cuomo2Cristina Pagano3Federica Trio4Davide Costabile5Giulia de Riso6Francesca Sveva Cicala7Maddalena Raia8Raduan Ahmed Franca9Marialaura Del Basso De Caro10Domenico Sorrentino11Giovanna Navarra12Laura Coppola13Lorella Tripodi14Lucio Pastore15Juergen Hench16Stephan Frank17Claudio Schonauer18Giuseppe Catapano19Maurizio Bifulco20Lorenzo Chiariotti21Roberta Visconti22CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”Department of Molecular Medicine and Medical Biotechnologies, University of Napoli “Federico II”CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”Department of Molecular Medicine and Medical Biotechnologies, University of Napoli “Federico II”CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”Pathology Unit, University of Napoli “Federico II”Pathology Unit, University of Napoli “Federico II”CEINGE-Advanced Biotechnologies “Franco Salvatore”Department of Molecular Medicine and Medical Biotechnologies, University of Napoli “Federico II”Department of Molecular Medicine and Medical Biotechnologies, University of Napoli “Federico II”CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”Institute for Medical Genetics and Pathology, Basel University HospitalsInstitute for Medical Genetics and Pathology, Basel University HospitalsNeurosurgery Unit, “Antonio Cardarelli” HospitalNeurosurgery Unit, “Ospedale del Mare” HospitalDepartment of Molecular Medicine and Medical Biotechnologies, University of Napoli “Federico II”CEINGE-Advanced Biotechnologies “Franco Salvatore”CEINGE-Advanced Biotechnologies “Franco Salvatore”Abstract Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.https://doi.org/10.1038/s41419-023-06167-3 |
| spellingShingle | Rosa Della Monica Michela Buonaiuto Mariella Cuomo Cristina Pagano Federica Trio Davide Costabile Giulia de Riso Francesca Sveva Cicala Maddalena Raia Raduan Ahmed Franca Marialaura Del Basso De Caro Domenico Sorrentino Giovanna Navarra Laura Coppola Lorella Tripodi Lucio Pastore Juergen Hench Stephan Frank Claudio Schonauer Giuseppe Catapano Maurizio Bifulco Lorenzo Chiariotti Roberta Visconti Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth Cell Death and Disease |
| title | Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth |
| title_full | Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth |
| title_fullStr | Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth |
| title_full_unstemmed | Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth |
| title_short | Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth |
| title_sort | targeted inhibition of the methyltransferase setd8 synergizes with the wee1 inhibitor adavosertib in restraining glioblastoma growth |
| url | https://doi.org/10.1038/s41419-023-06167-3 |
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