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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Autores principales:	Emilie Logie, Bart Van Puyvelde, Bart Cuypers, Anne Schepers, Herald Berghmans, Jelle Verdonck, Kris Laukens, Lode Godderis, Maarten Dhaenens, Dieter Deforce, Wim Vanden Berghe
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ferroptosis multiple myeloma DNA methylation iron histone post-translational modifications epigenome Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/128c5ee5fc334f36a213008aab24613c
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spelling	oai:doaj.org-article:128c5ee5fc334f36a213008aab24613c2021-11-25T17:54:35ZFerroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence10.3390/ijms2222122341422-00671661-6596https://doaj.org/article/128c5ee5fc334f36a213008aab24613c2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12234https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Disease 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.Emilie LogieBart Van PuyveldeBart CuypersAnne SchepersHerald BerghmansJelle VerdonckKris LaukensLode GodderisMaarten DhaenensDieter DeforceWim Vanden BergheMDPI AGarticleferroptosismultiple myelomaDNA methylationironhistone post-translational modificationsepigenomeBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12234, p 12234 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ferroptosis multiple myeloma DNA methylation iron histone post-translational modifications epigenome Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ferroptosis multiple myeloma DNA methylation iron histone post-translational modifications epigenome Biology (General) QH301-705.5 Chemistry QD1-999 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
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.
format	article
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
title	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_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_sort	ferroptosis induction in multiple myeloma cells triggers dna methylation and histone modification changes associated with cellular senescence
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/128c5ee5fc334f36a213008aab24613c
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Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence

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