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Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma
Glioblastoma is the most common and aggressive primary tumor of the central nervous system with poor outcome. Current gold standard treatment is surgical resection followed by a combination of radio- and chemotherapy. Efficacy of temozolomide (TMZ), the primary chemotherapeutic agent, depends on the...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475512/ https://www.ncbi.nlm.nih.gov/pubmed/37634280 http://dx.doi.org/10.1016/j.neo.2023.100929 |
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author | Han, Xinyu Abdallah, Mohammed O.E. Breuer, Peter Stahl, Fabian Bakhit, Yousuf Potthoff, Anna-Laura Pregler, Barbara E.F. Schneider, Matthias Waha, Andreas Wüllner, Ullrich Evert, Bernd O. |
author_facet | Han, Xinyu Abdallah, Mohammed O.E. Breuer, Peter Stahl, Fabian Bakhit, Yousuf Potthoff, Anna-Laura Pregler, Barbara E.F. Schneider, Matthias Waha, Andreas Wüllner, Ullrich Evert, Bernd O. |
author_sort | Han, Xinyu |
collection | PubMed |
description | Glioblastoma is the most common and aggressive primary tumor of the central nervous system with poor outcome. Current gold standard treatment is surgical resection followed by a combination of radio- and chemotherapy. Efficacy of temozolomide (TMZ), the primary chemotherapeutic agent, depends on the DNA methylation status of the O6-methylguanine DNA methyltransferase (MGMT), which has been identified as a prognostic biomarker in glioblastoma patients. Clinical studies revealed that glioblastoma patients with hypermethylated MGMT promoter have a better response to TMZ treatment and a significantly improved overall survival. In this study, we thus used the CRISPRoff genome editing tool to mediate targeted DNA methylation within the MGMT promoter region. The system carrying a CRISPR-deactivated Cas9 (dCas9) fused with a methyltransferase (Dnmt3A/3L) domain downregulated MGMT expression in TMZ-resistant human glioblastoma cell lines through targeted DNA methylation. The reduction of MGMT expression levels reversed TMZ resistance in TMZ-resistant glioblastoma cell lines resulting in TMZ induced dose-dependent cell death rates. In conclusion, we demonstrate targeted RNA-guided methylation of the MGMT promoter as a promising tool to overcome chemoresistance and improve the cytotoxic effect of TMZ in glioblastoma. |
format | Online Article Text |
id | pubmed-10475512 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104755122023-09-05 Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma Han, Xinyu Abdallah, Mohammed O.E. Breuer, Peter Stahl, Fabian Bakhit, Yousuf Potthoff, Anna-Laura Pregler, Barbara E.F. Schneider, Matthias Waha, Andreas Wüllner, Ullrich Evert, Bernd O. Neoplasia Original Research Glioblastoma is the most common and aggressive primary tumor of the central nervous system with poor outcome. Current gold standard treatment is surgical resection followed by a combination of radio- and chemotherapy. Efficacy of temozolomide (TMZ), the primary chemotherapeutic agent, depends on the DNA methylation status of the O6-methylguanine DNA methyltransferase (MGMT), which has been identified as a prognostic biomarker in glioblastoma patients. Clinical studies revealed that glioblastoma patients with hypermethylated MGMT promoter have a better response to TMZ treatment and a significantly improved overall survival. In this study, we thus used the CRISPRoff genome editing tool to mediate targeted DNA methylation within the MGMT promoter region. The system carrying a CRISPR-deactivated Cas9 (dCas9) fused with a methyltransferase (Dnmt3A/3L) domain downregulated MGMT expression in TMZ-resistant human glioblastoma cell lines through targeted DNA methylation. The reduction of MGMT expression levels reversed TMZ resistance in TMZ-resistant glioblastoma cell lines resulting in TMZ induced dose-dependent cell death rates. In conclusion, we demonstrate targeted RNA-guided methylation of the MGMT promoter as a promising tool to overcome chemoresistance and improve the cytotoxic effect of TMZ in glioblastoma. Neoplasia Press 2023-08-25 /pmc/articles/PMC10475512/ /pubmed/37634280 http://dx.doi.org/10.1016/j.neo.2023.100929 Text en © 2023 Published by Elsevier Inc. 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/). |
spellingShingle | Original Research Han, Xinyu Abdallah, Mohammed O.E. Breuer, Peter Stahl, Fabian Bakhit, Yousuf Potthoff, Anna-Laura Pregler, Barbara E.F. Schneider, Matthias Waha, Andreas Wüllner, Ullrich Evert, Bernd O. Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title | Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title_full | Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title_fullStr | Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title_full_unstemmed | Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title_short | Downregulation of MGMT expression by targeted editing of DNA methylation enhances temozolomide sensitivity in glioblastoma |
title_sort | downregulation of mgmt expression by targeted editing of dna methylation enhances temozolomide sensitivity in glioblastoma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475512/ https://www.ncbi.nlm.nih.gov/pubmed/37634280 http://dx.doi.org/10.1016/j.neo.2023.100929 |
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