Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence
Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated c...
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| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/22/12234 |
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| author | Emilie Logie Bart Van Puyvelde Bart Cuypers Anne Schepers Herald Berghmans Jelle Verdonck Kris Laukens Lode Godderis Maarten Dhaenens Dieter Deforce Wim Vanden Berghe |
| author_facet | Emilie Logie Bart Van Puyvelde Bart Cuypers Anne Schepers Herald Berghmans Jelle Verdonck Kris Laukens Lode Godderis Maarten Dhaenens Dieter Deforce Wim Vanden Berghe |
| author_sort | Emilie Logie |
| collection | DOAJ |
| description | Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds. |
| first_indexed | 2024-03-10T05:26:16Z |
| format | Article |
| id | doaj.art-128c5ee5fc334f36a213008aab24613c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:26:16Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-128c5ee5fc334f36a213008aab24613c2023-11-22T23:39:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221223410.3390/ijms222212234Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular SenescenceEmilie Logie0Bart Van Puyvelde1Bart Cuypers2Anne Schepers3Herald Berghmans4Jelle Verdonck5Kris Laukens6Lode Godderis7Maarten Dhaenens8Dieter Deforce9Wim Vanden Berghe10Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, BelgiumLaboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, BelgiumBiomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, BelgiumCenter of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Edegem, BelgiumLaboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, BelgiumCenter for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, BelgiumBiomedical Informatics Network Antwerp (Biomina), Department of Computer Science, University of Antwerp, 2610 Antwerp, BelgiumCenter for Environment and Health, Department of Public Health and Primary Care, KU Leuven, 3000 Leuven, BelgiumLaboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, BelgiumLaboratory of Pharmaceutical Biotechnology, Proteomics and Mass Spectrometry Department, Ghent University, 9000 Ghent, BelgiumLaboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES) and Integrated Personalized and Precision Oncology Network (IPPON), Department of Biomedical Sciences, University of Antwerp, 2610 Wilrijk, BelgiumDisease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds.https://www.mdpi.com/1422-0067/22/22/12234ferroptosismultiple myelomaDNA methylationironhistone post-translational modificationsepigenome |
| spellingShingle | Emilie Logie Bart Van Puyvelde Bart Cuypers Anne Schepers Herald Berghmans Jelle Verdonck Kris Laukens Lode Godderis Maarten Dhaenens Dieter Deforce Wim Vanden Berghe Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence International Journal of Molecular Sciences ferroptosis multiple myeloma DNA methylation iron histone post-translational modifications epigenome |
| title | Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence |
| title_full | Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence |
| title_fullStr | Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence |
| title_full_unstemmed | Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence |
| title_short | Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence |
| title_sort | ferroptosis induction in multiple myeloma cells triggers dna methylation and histone modification changes associated with cellular senescence |
| topic | ferroptosis multiple myeloma DNA methylation iron histone post-translational modifications epigenome |
| url | https://www.mdpi.com/1422-0067/22/22/12234 |
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