A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis
Abstract Epigenetic changes are present in all human cancers and are responsible for switching on or off genes, thus controlling tumor cell transcriptome. These changes occur through DNA methylation, histone modifiers and readers, chromatin remodelers, and microRNAs. The histone H3 methyl-transferas...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07607-y |
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| author | Marta C. Nocito Constanze Hantel Antonio M. Lerario Fabrizio Mastrorocco Luca De Martino Clara Musicco Ida D. Perrotta Mariafrancesca Scalise Cesare Indiveri Sergio Giannattasio Pierre Val Marilena Lanzino Vincenzo Pezzi Ivan Casaburi Rosa Sirianni |
| author_facet | Marta C. Nocito Constanze Hantel Antonio M. Lerario Fabrizio Mastrorocco Luca De Martino Clara Musicco Ida D. Perrotta Mariafrancesca Scalise Cesare Indiveri Sergio Giannattasio Pierre Val Marilena Lanzino Vincenzo Pezzi Ivan Casaburi Rosa Sirianni |
| author_sort | Marta C. Nocito |
| collection | DOAJ |
| description | Abstract Epigenetic changes are present in all human cancers and are responsible for switching on or off genes, thus controlling tumor cell transcriptome. These changes occur through DNA methylation, histone modifiers and readers, chromatin remodelers, and microRNAs. The histone H3 methyl-transferase EZH2 gene is overexpressed in several cancer types, including adrenocortical carcinoma (ACC), a rare cancer still lacking a targeted therapy. EZH2 inhibitors (EZH2i) have been tested in several clinical trials, but their effectiveness was limited by the toxic effects of the therapeutic doses. We tested several EZH2i on ACC cells, and observed a significant reduction in cell growth only with doses much higher than those required to prevent H3 methylation. We found that all tested EZH2i doses affected lipid metabolism genes, ROS, and glutathione production. Transcript changes correlated with metabolic data, which suggested the effects of EZH2i on ferroptosis. We found that EZH2i dose-dependently increased SLC7A11/glutathione axis and glutathione peroxidase-4 (GPX4), required to counteract lipid peroxidation and ferroptosis. A GPX4 inhibitor synergized with EZH2i, making low doses - which otherwise do not affect cell viability - able to significantly reduce ACC cell growth in vitro and in vivo. Importantly, we found that the anti-ferroptosis defense mechanism induced by EZH2i is a common response for several aggressive tumor phenotypes, uncovering a general co-targetable mechanism that could limit EZH2i effectiveness. Correcting this antioxidant response by ferroptosis inducers may be a new combination therapy that will easily find clinical applications. |
| format | Article |
| id | doaj-art-dfe7e414c9ee46b6aa905966cfd565c6 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-dfe7e414c9ee46b6aa905966cfd565c62025-08-20T02:27:06ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111510.1038/s41419-025-07607-yA targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosisMarta C. Nocito0Constanze Hantel1Antonio M. Lerario2Fabrizio Mastrorocco3Luca De Martino4Clara Musicco5Ida D. Perrotta6Mariafrancesca Scalise7Cesare Indiveri8Sergio Giannattasio9Pierre Val10Marilena Lanzino11Vincenzo Pezzi12Ivan Casaburi13Rosa Sirianni14Department of Pharmacy and Health and Nutritional Sciences, University of CalabriaDepartment of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), 8091Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Medical SchoolInstitute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council of Italy (CNR)Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council of Italy (CNR)Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council of Italy (CNR)Centre for Microscopy and Microanalysis (CM2), Department of Biology, Biology, Ecology and Earth Sciences (DiBEST), University of CalabriaDepartment of Biology, Ecology and Earth Sciences (DiBEST), University of CalabriaInstitute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council of Italy (CNR)Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council of Italy (CNR)France iGReD (Institute of Genetics, Reproduction and Development), CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri DunantDepartment of Pharmacy and Health and Nutritional Sciences, University of CalabriaDepartment of Pharmacy and Health and Nutritional Sciences, University of CalabriaDepartment of Pharmacy and Health and Nutritional Sciences, University of CalabriaDepartment of Pharmacy and Health and Nutritional Sciences, University of CalabriaAbstract Epigenetic changes are present in all human cancers and are responsible for switching on or off genes, thus controlling tumor cell transcriptome. These changes occur through DNA methylation, histone modifiers and readers, chromatin remodelers, and microRNAs. The histone H3 methyl-transferase EZH2 gene is overexpressed in several cancer types, including adrenocortical carcinoma (ACC), a rare cancer still lacking a targeted therapy. EZH2 inhibitors (EZH2i) have been tested in several clinical trials, but their effectiveness was limited by the toxic effects of the therapeutic doses. We tested several EZH2i on ACC cells, and observed a significant reduction in cell growth only with doses much higher than those required to prevent H3 methylation. We found that all tested EZH2i doses affected lipid metabolism genes, ROS, and glutathione production. Transcript changes correlated with metabolic data, which suggested the effects of EZH2i on ferroptosis. We found that EZH2i dose-dependently increased SLC7A11/glutathione axis and glutathione peroxidase-4 (GPX4), required to counteract lipid peroxidation and ferroptosis. A GPX4 inhibitor synergized with EZH2i, making low doses - which otherwise do not affect cell viability - able to significantly reduce ACC cell growth in vitro and in vivo. Importantly, we found that the anti-ferroptosis defense mechanism induced by EZH2i is a common response for several aggressive tumor phenotypes, uncovering a general co-targetable mechanism that could limit EZH2i effectiveness. Correcting this antioxidant response by ferroptosis inducers may be a new combination therapy that will easily find clinical applications.https://doi.org/10.1038/s41419-025-07607-y |
| spellingShingle | Marta C. Nocito Constanze Hantel Antonio M. Lerario Fabrizio Mastrorocco Luca De Martino Clara Musicco Ida D. Perrotta Mariafrancesca Scalise Cesare Indiveri Sergio Giannattasio Pierre Val Marilena Lanzino Vincenzo Pezzi Ivan Casaburi Rosa Sirianni A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis Cell Death and Disease |
| title | A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| title_full | A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| title_fullStr | A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| title_full_unstemmed | A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| title_short | A targetable antioxidant defense mechanism to EZH2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| title_sort | targetable antioxidant defense mechanism to ezh2 inhibitors enhances tumor cell vulnerability to ferroptosis |
| url | https://doi.org/10.1038/s41419-025-07607-y |
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