Dual roles of demethylation in cancer treatment and cardio-function recovery.
Dual roles of demethylation in cancer treatment and cardio-function recovery.
复制标题
DOI：
10.1016/j.redox.2023.102785
复制
发表时间：
2023-08
期刊：
影响因子：
11.4
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Li X;Shen D;Zhu Z;Lyu D;He C;Sun Y;Li J;Lu Q;Wang G
没有有效的治疗靶点或策略同时抑制肿瘤生长和促进心脏功能恢复。在这里，我们分析了癌症治疗和心脏修复的靶点，其中去甲基化是这些候选名单中的一个共同因素。由于DNA甲基转移酶1（DNMT 1）主要对甲基化起反应，筛选天然化合物库，鉴定薯蓣皂苷为广泛用于心脏病的针对DNMT 1的新型药物。薯蓣皂苷被发现可以降低DNMT活性并抑制乳腺癌细胞的生长。结合RNA-seq和MeDIP-seq分析，薯蓣皂苷处理后，抗氧化基因启动子发生去甲基化，招募NRF 2并提高其表达。在Nrf 2基因敲除小鼠中，薯蓣皂苷的心脏保护作用被Nrf 2缺失阻断。此外，在肥大的荷瘤小鼠中，观察到薯蓣皂苷抑制肿瘤生长并同时减轻心脏损伤。本研究首次发现薯蓣皂苷是一种具有抗癌和保护心脏双重功能的新型去甲基化剂。薯蓣皂苷消除癌细胞和心肌细胞中的甲基化。薯蓣皂苷去甲基化修饰的抗氧化基因的启动子转录调节D由NRF 2在肥大。薯蓣皂苷首次为肿瘤和心血管疾病的联合治疗提供了新的策略。
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. Dioscin abolishes methylation in cancer cells and cardiomyocytes. Dioscin demethylates the modified promoters of antioxidant genes transcriptionally regulatedD by NRF2 in hypertrophy. Dioscin provides a novel strategy for the joint treatment of cancer and cardiovascular diseases for the first time.
登录
查看更多内容
影响因子：
4.7
作者：
Rice, JC;Ozcelik, H;Futscher, BW
通讯作者：
Futscher, BW
影响因子：
64.5
作者：
Okano, M;Bell, DW;Li, E
通讯作者：
Li, E
影响因子：
120.7
作者：
Jemal, A;Ward, E;Thun, M
通讯作者：
Thun, M
影响因子：
18.2
作者：
Luis Zamorano, Jose;Lancellotti, Patrizio;Ringwald, Juergen
通讯作者：
Ringwald, Juergen
影响因子：
37.8
作者：
Papait, Roberto;Serio, Simone;Condorelli, Gianluigi
通讯作者：
Condorelli, Gianluigi