Dual roles of demethylation in cancer treatment and cardio-function recovery

Li, Xinuo; Shen, Dehong; Zhu, Zheying; Lyu, Dayin; He, Chang; Sun, Yuan; Li, Jinran; Lu, Qiulun; Wang, Guangji

Abstract

There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for cancer treatments and cardiac repair, with demethylation emerging as a common factor in these candidate lists. As DNA methyltransferase 1 (DNMT1) majorly responds to methylation, a natural compound library is screened, identifying dioscin as a novel agent targeted at DNMT1, widely used for heart diseases. Dioscin was found to reduce DNMT activities and inhibits growth in breast cancer cells. Combined with analyses of RNA-seq and MeDIP-seq, the promoters of antioxidant genes were demethylated after dioscin, recruiting NRF2 and elevating their expression. In Nrf2 knockout mice, the cardiac protection role of dioscin was blocked by Nrf2-loss. Furthermore, in tumour-bearing mice with hypertrophy, dioscin was observed to inhibit tumour growth and alleviate cardiac injury simultaneously. This study is the first to identify dioscin as a novel demethylation agent with dual functions of anti-cancer and cardio-protection.

Citation

Li, X., Shen, D., Zhu, Z., Lyu, D., He, C., Sun, Y., …Wang, G. (2023). Dual roles of demethylation in cancer treatment and cardio-function recovery. Redox Biology, 64, Article 102785. https://doi.org/10.1016/j.redox.2023.102785

• Journal Article Type: Article
• Acceptance Date: Jun 13, 2023
• Online Publication Date: Jun 14, 2023
• Publication Date: 2023-08
• Deposit Date: Jun 24, 2023
• Publicly Available Date: Jun 30, 2023
• Journal: Redox Biology
• Print ISSN: 2213-2317
• Electronic ISSN: 2213-2317
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 64
• Article Number: 102785
• DOI: https://doi.org/10.1016/j.redox.2023.102785
• Keywords: DNMT inhibitors; Demethylation; NRF2; Hypertrophy; Cancer treatment
• Public URL: https://nottingham-repository.worktribe.com/output/22203613
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2213231723001866?via%3Dihub