Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence

被引：37

作者：

Logie, Emilie ^{[1
,2
]}

Van Puyvelde, Bart ^{[3
]}

Cuypers, Bart ^{[4
]}

Schepers, Anne ^{[5
,6
]}

Berghmans, Herald ^{[1
,2
]}

Verdonck, Jelle ^{[7
]}

Laukens, Kris ^{[4
]}

Godderis, Lode ^{[7
,8
]}

Dhaenens, Maarten ^{[3
]}

Deforce, Dieter ^{[3
]}

Vanden Berghe, Wim ^{[1
,2
]}

机构：

[1] Univ Antwerp, Dept Biomed Sci, Lab Prot Sci Prote & Epigenet Signaling PPES, B-2610 Antwerp, Belgium

[2] Univ Antwerp, Dept Biomed Sci, Integrated Personalized & Precis Oncol Network IP, B-2610 Antwerp, Belgium

[3] Univ Ghent, Prote & Mass Spectrometry Dept, Lab Pharmaceut Biotechnol, B-9000 Ghent, Belgium

[4] Univ Antwerp, Dept Comp Sci, Biomed Informat Network Antwerp Biomina, B-2610 Antwerp, Belgium

[5] Univ Antwerp, Ctr Med Genet, B-2650 Edegem, Belgium

[6] Antwerp Univ Hosp, B-2650 Edegem, Belgium

[7] Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Ctr Environm & Hlth, B-3000 Leuven, Belgium

[8] IDEWE, External Serv Prevent & Protect Work, B-3001 Heverlee, Belgium

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2021年 / 22卷 / 22期

关键词：

ferroptosis; multiple myeloma; DNA methylation; iron; histone post-translational modifications; epigenome; CHROMATIN MODIFIERS; EXPRESSION; H2A.Z; METABOLISM; INHIBITION; ACCUMULATION; ACTIVATION; RESISTANCE; MECHANISM; HALLMARKS;

D O I：

10.3390/ijms222212234

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：25