Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway

• Published in: Annals of hematology 2024-07, Vol.103 (7), p.2405-2417
• Main Authors: Zhang, Yu, Wang, Xiaoshun, Li, Xiaoqi, Xiong, Xingfang, Xue, Renyu, Zang, Lanlan, Wang, Zhiqiang, Wang, Lijuan
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Proliferation - drug effects; Enzyme Inhibitors - pharmacology; Ferroptosis; Ferroptosis - drug effects; Hematology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Medicine; Medicine & Public Health; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-E2-Related Factor 2 - metabolism; Oncology; Protein expression; Signal Transduction - drug effects
• ISSN: 0939-5555; 1432-0584; 1432-0584
• DOI: 10.1007/s00277-024-05728-6

Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.