Dual roles of demethylation in cancer treatment and cardio-function recovery
Xinuo Li,
Dehong Shen,
Zheying Zhu,
Dayin Lyu,
Chang He,
Yuan Sun,
Jinran Li,
Qiulun Lu,
Guangji Wang
Affiliations
Xinuo Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
Dehong Shen
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
Zheying Zhu
School of Pharmacy, The University of Nottingham, Nottingham, NG7 2RD, UK
Dayin Lyu
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
Chang He
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China
Yuan Sun
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
Jinran Li
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
Qiulun Lu
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China; Corresponding author. 639 Longmian Avenue, Nanjing, 211166, Jiangsu, China.
Guangji Wang
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China; Corresponding author. Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China.
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.
