IDO1 Inhibits Ferroptosis by Regulating FTO-mediated M6A Methylation and SLC7A11 MRNA Stability During Glioblastoma Progression

Overview

Journal Cell Death Discov

Date 2025 Jan 25

PMID 39863603

Authors

Qianting Tian

Guixue Dan

Xuyan Wang

Jiamei Zhu

Chaochun Chen

Dekun Tang

Ziming Wang

Dan Chen

Shan Lei

Chao Yang

Houmei Wang

Bing Guo

Bangming Jin

Tengxiang Chen

Lei Tang

Affiliations

Soon will be listed here.

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) has been recognized as an enzyme involved in tryptophan catabolism with immunosuppressive ability. This study determined to investigate the impact of IDO1 on glioblastoma multiforme (GBM) cells. Here, we showed that the expression of IDO1 was markedly increased in patients with glioma and associated with GBM progression. IDO1 overexpression suppressed ferroptotic cell death, reduced ROS and lipid peroxide generation in GBM cells. IDO1 expression increased the SLC7A11 mRNA stability through FTO-dependent m6A methylation. Mechanistically, IDO1 promoted the AhR expression and nuclear translocation, thus facilitating AhR recruitment at the promoter regions of FTO gene and negatively regulating its transcription. These findings demonstrate that IDO1 facilitates GBM progression by inhibiting SLC7A11-dependent ferroptosis through an IDO1-AhR-FTO axis-mediated m6A methylation mechanism.

References

Verdugo E, Puerto I, Medina M . An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment. Cancer Commun (Lond). 2022; 42(11):1083-1111. PMC: 9648390. DOI: 10.1002/cac2.12361. View

Stoyanov G, Dzhenkov D, Ghenev P, Iliev B, Enchev Y, Tonchev A . Cell biology of glioblastoma multiforme: from basic science to diagnosis and treatment. Med Oncol. 2018; 35(3):27. DOI: 10.1007/s12032-018-1083-x. View

Yang Y, Hsu P, Chen Y, Yang Y . Dynamic transcriptomic mA decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28(6):616-624. PMC: 5993786. DOI: 10.1038/s41422-018-0040-8. View

Deng X, Su R, Weng H, Huang H, Li Z, Chen J . RNA N-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018; 28(5):507-517. PMC: 5951805. DOI: 10.1038/s41422-018-0034-6. View

Huai W, Zhao R, Song H, Zhao J, Zhang L, Zhang L . Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat Commun. 2014; 5:4738. DOI: 10.1038/ncomms5738. View

Singleman C, Holtzman N . PCB and TCDD derived embryonic cardiac defects result from a novel AhR pathway. Aquat Toxicol. 2021; 233:105794. DOI: 10.1016/j.aquatox.2021.105794. View

Muller A, Manfredi M, Zakharia Y, Prendergast G . Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Semin Immunopathol. 2018; 41(1):41-48. DOI: 10.1007/s00281-018-0702-0. View

Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing K . IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol. 2018; 15(5):447-457. PMC: 6068130. DOI: 10.1038/cmi.2017.143. View

Zhai L, Ladomersky E, Lauing K, Wu M, Genet M, Gritsina G . Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival. Clin Cancer Res. 2017; 23(21):6650-6660. PMC: 5850948. DOI: 10.1158/1078-0432.CCR-17-0120. View

10.

Zhou S, Li J, Chen H, Zeng Y, Yuan W, Shi Y . FTO-Nrf2 axis regulates bisphenol F-induced leydig cell toxicity in an m6A-YTHDF2-dependent manner. Environ Pollut. 2023; 325:121393. DOI: 10.1016/j.envpol.2023.121393. View

11.

Zhai L, Bell A, Ladomersky E, Lauing K, Bollu L, Sosman J . Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Front Immunol. 2020; 11:1185. PMC: 7308527. DOI: 10.3389/fimmu.2020.01185. View

12.

Fiore A, Zeitler L, Russier M, Gross A, Hiller M, Parker J . Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling. Mol Cell. 2022; 82(5):920-932.e7. DOI: 10.1016/j.molcel.2022.02.007. View

13.

Visvanathan A, Patil V, Arora A, Hegde A, Arivazhagan A, Santosh V . Essential role of METTL3-mediated mA modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2017; 37(4):522-533. DOI: 10.1038/onc.2017.351. View

14.

Liu J, Kang R, Tang D . Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2021; 289(22):7038-7050. DOI: 10.1111/febs.16059. View

15.

Zhao J, Ma X, Gao P, Han X, Zhao P, Xie F . Advancing glioblastoma treatment by targeting metabolism. Neoplasia. 2024; 51:100985. PMC: 10950892. DOI: 10.1016/j.neo.2024.100985. View

16.

Liang D, Minikes A, Jiang X . Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022; 82(12):2215-2227. PMC: 9233073. DOI: 10.1016/j.molcel.2022.03.022. View

17.

Kou Z, Tran F, Colon T, Shteynfeld Y, Noh S, Chen F . AhR signaling modulates Ferroptosis by regulating SLC7A11 expression. Toxicol Appl Pharmacol. 2024; 486:116936. DOI: 10.1016/j.taap.2024.116936. View

18.

Zeng X, Lu Y, Zeng T, Liu W, Huang W, Yu T . RNA demethylase FTO participates in malignant progression of gastric cancer by regulating SP1-AURKB-ATM pathway. Commun Biol. 2024; 7(1):800. PMC: 11220007. DOI: 10.1038/s42003-024-06477-y. View

19.

Liu L, He J, Sun G, Huang N, Bian Z, Xu C . The N6-methyladenosine modification enhances ferroptosis resistance through inhibiting SLC7A11 mRNA deadenylation in hepatoblastoma. Clin Transl Med. 2022; 12(5):e778. PMC: 9076012. DOI: 10.1002/ctm2.778. View

20.

Zhang Y, Geng X, Li Q, Xu J, Tan Y, Xiao M . m6A modification in RNA: biogenesis, functions and roles in gliomas. J Exp Clin Cancer Res. 2020; 39(1):192. PMC: 7500025. DOI: 10.1186/s13046-020-01706-8. View