We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence.
- Authors
Logie, Emilie; Van Puyvelde, Bart; Cuypers, Bart; Schepers, Anne; Berghmans, Herald; Verdonck, Jelle; Laukens, Kris; Godderis, Lode; Dhaenens, Maarten; Deforce, Dieter; Vanden Berghe, Wim
- Abstract
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.
- Subjects
CELLULAR aging; MULTIPLE myeloma; DNA methylation; HISTONE methylation; CELL death; IRON metabolism; HISTONES
- Publication
International Journal of Molecular Sciences, 2021, Vol 22, Issue 22, p12234
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms222212234