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Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway
Yu Zhang1,2, Xiaoshun Wang3, Xiaoqi Li2,4
1Postgraduate Training Base of Linyi People's Hospital, Guangzhou University of Chinese Medicine, Linyi, China.
Abstract:
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.
Insights
The novel methyltransferase inhibitor DCG066 halts multiple myeloma (MM) cell growth by inducing ferroptosis. This occurs through the Nrf2/HO-1 pathway, offering a new therapeutic strategy for MM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Mechanisms
Background:
- Multiple myeloma (MM) is a hematologic neoplasm where epigenetic modifications influence its development and drug resistance.
- Ferroptosis, a programmed cell death pathway, is increasingly recognized for its role in MM progression.
Purpose of the Study:
- To elucidate the mechanism of action of the novel methyltransferase inhibitor DCG066 in multiple myeloma cells.
- To investigate the role of ferroptosis and the Nrf2/HO-1 pathway in DCG066's anti-myeloma effects.
Main Methods:
- Treatment of MM cells with DCG066 (5µM) and assessment of proliferation, cell death markers, and protein expression.
- Utilized ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ) to validate findings.
- Measured intracellular reactive oxygen species (ROS), iron, malondialdehyde (MDA), and glutathione (GSH) levels.
Main Results:
- DCG066 significantly inhibited MM cell proliferation and induced ferroptosis, evidenced by increased ROS, iron, and MDA, and decreased GSH.
- DCG066 treatment reduced protein expression of SLC7A11, GPX4, Nrf2, and HO-1, while increasing Keap1 and decreasing heat shock proteins (HSP70, HSP90, HSPB1).
- These effects were reversed by Fer-1 and TBHQ, confirming the involvement of ferroptosis and the Nrf2 pathway.
Conclusions:
- DCG066 effectively inhibits multiple myeloma proliferation by inducing ferroptosis.
- The mechanism involves the downregulation of the Nrf2/HO-1 pathway, highlighting its potential as a therapeutic target in MM.
