DNMT1 通过联合调节 DNA 和 mRNA 胞嘧啶 5 甲基化来确定骨肉瘤细胞对细胞凋亡的抵抗力。
DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation.
发表日期：2023 Dec
作者：
Dongxing Shao, Cihang Liu, Yingying Wang, Jing Lin, Xiaolei Cheng, Pei Han, Zhen Li, Dongdong Jian, Junwei Nie, Mingyang Jiang, Yuanzhi Wei, Junyue Xing, Zhiping Guo, Wengong Wang, Xia Yi, Hao Tang
来源：
Epigenetics & Chromatin
摘要：
细胞凋亡是化疗治疗人类癌症的核心机制。据记载，DNA 和 mRNA 上安装的 5-甲基胞嘧啶 (m5C) 修饰可独立调节细胞凋亡。然而，它们在细胞凋亡中的相互作用或串扰尚未被探索。在这里，我们报道了 DNMT1 的启动子甲基化与 NSun2 的 mRNA 甲基化协调调节骨肉瘤细胞凋亡。 DNMT1在化疗药物引发的骨肉瘤细胞凋亡过程中被诱导，而NSun2的表达被抑制。发现 DNMT1 通过甲基化 NSun2 启动子来抑制 NSun2 表达。此外，DNMT1和NSun2分别通过DNA和mRNA甲基化调节抗凋亡基因AXL、NOTCH2和YAP1。暴露于顺铂或多柔比星后，DNMT1 升高通过增强启动子甲基化以及 NSun2 消融介导的 mRNA 甲基化减弱，显着降低了这些抗凋亡基因的表达，从而导致骨肉瘤细胞凋亡。总的来说，我们的研究结果确立了 DNA 和 RNA 胞嘧啶甲基化之间的串扰在确定骨肉瘤化疗期间对细胞凋亡的抵抗力方面的重要性，为未来骨肉瘤的治疗提供了新的思路，并为不同表观遗传水平的基因表达控制添加了额外的层。© 2023作者。 FASEB 期刊由 Wiley periodicals LLC 代表美国实验生物学学会联合会出版。
Cellular apoptosis is a central mechanism leveraged by chemotherapy to treat human cancers. 5-Methylcytosine (m5C) modifications installed on both DNA and mRNA are documented to regulate apoptosis independently. However, the interplay or crosstalk between them in cellular apoptosis has not yet been explored. Here, we reported that promoter methylation by DNMT1 coordinated with mRNA methylation by NSun2 to regulate osteosarcoma cell apoptosis. DNMT1 was induced during osteosarcoma cell apoptosis triggered by chemotherapeutic drugs, whereas NSun2 expression was suppressed. DNMT1 was found to repress NSun2 expression by methylating the NSun2 promoter. Moreover, DNMT1 and NSun2 regulate the anti-apoptotic genes AXL, NOTCH2, and YAP1 through DNA and mRNA methylation, respectively. Upon exposure to cisplatin or doxorubicin, DNMT1 elevation drastically reduced the expression of these anti-apoptotic genes via enhanced promoter methylation coupled with NSun2 ablation-mediated attenuation of mRNA methylation, thus rendering osteosarcoma cells to apoptosis. Collectively, our findings establish crosstalk of importance between DNA and RNA cytosine methylations in determining osteosarcoma resistance to apoptosis during chemotherapy, shedding new light on future treatment of osteosarcoma, and adding additional layers to the control of gene expression at different epigenetic levels.© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.