Lu Yanan, Song Shuting, Jiang Xiaoxue, Meng Qiuyu, Wang Chen, Li Xiaonan, Yang Yuxin, Xin Xiaoru, Zheng Qidi, Wang Liyan, Pu Hu, Gui Xin, Li Tianming, Lu Dongdong
Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Mol Ther Nucleic Acids. 2019 Mar 1;14:171-183. doi: 10.1016/j.omtn.2018.11.010. Epub 2018 Nov 24.
miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex's occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.
miR675在多种人类肿瘤组织中高表达，并正向调节细胞进程。在此，我们证明miR675促进人间充质干细胞的恶性转化。机制上，我们发现miR675增强了多聚泛素结合蛋白p62的表达。有趣的是，P62与SETD2竞争结合组蛋白H3，进而显著降低SETD2与底物组蛋白H3的结合能力，极大地引发组蛋白H3第36位赖氨酸三甲基化（H3K36me3）的减少。由此，H3K36me3-hMSH6-SKP2三元复合物显著减少。值得注意的是，三元复合物在染色体上的占据能力绝对降低，阻止其进行DNA损伤修复。凭借SKP2对与错配DNA结合的衰老组蛋白H3.3的还原降解能力，衰老组蛋白H3.3的修复延迟。因此，错配DNA逃避修复，触发多个细胞周期相关基因的异常表达，导致间充质干细胞的恶性转化。这些观察结果强烈表明，了解miR675的新功能将有助于开发针对多种癌症类型的新型治疗方法。
