组蛋白甲基转移酶Suv39h1与Wnt/β-连环蛋白信号通路的相互调控促进骨髓间充质干细胞在对苯二酚暴露中的增殖与抗凋亡
Mutual regulation between histone methyltransferase Suv39h1 and the Wnt/β-catenin signaling pathway promoted cell proliferation and inhibited apoptosis in bone marrow mesenchymal stem cells exposed to hydroquinone
DOI 原文链接
用sci-hub下载
如无法下载，请从 Sci-Hub 选择可用站点尝试。
影响因子:4.6
分区:医学3区 / 药学2区 毒理学2区
发表日期:2024 Nov
作者:
Tao Xu, Yilin Shen, Runmin Guo, Chiheng Luo, Yibo Niu, Zhilong Luo, Zhongxin Zhu, Zehui Wu, Xinyu Zhao, Hao Luo, Yuting Gao
DOI:
10.1016/j.tox.2024.153932
摘要
对苯二酚（HQ）是苯的代谢产物，常作为苯的体外研究模型，其与急性髓性白血病（AML）的发生密切相关。在苯和HQ引起的血液毒性中，细胞凋亡起着关键作用。然而，HQ的分子机制尚不清楚。研究表明，组蛋白甲基转移酶Suv39h1通过调节组蛋白H3K9me3参与细胞分裂和增殖的调控。同时，Wnt/β-连环蛋白信号通路在细胞增殖和凋亡中也扮演重要角色。因此，本研究旨在探讨Suv39h1及Wnt/β-连环蛋白信号通路在HQ对骨髓间充质干细胞（BMSCs）影响中的调控作用，以及其对细胞增殖和凋亡的影响。结果显示，HQ能升高Suv39h1和H3K9me3水平，并通过上调β-连环蛋白、Wnt2b、C-myc及Cyclin D1，下调Wnt5a，从而激活Wnt/β-连环蛋白信号通路，促进细胞生长并抑制凋亡。Suv39h1的敲低抑制了Wnt/β-连环蛋白通路；同时，抑制Wnt/β-连环蛋白通路也导致BMSCs中Suv39h1和H3K9me3水平的下降。两者通过下调Cyt-C、Bax、Caspase 3和Caspase 9的表达，以及上调Bcl-xl的表达，共同促进细胞增殖和抑制凋亡，从而缓解HQ对BMSCs的功能障碍。综上所述，Suv39h1与Wnt/β-连环蛋白信号通路在HQ对BMSCs作用中可能相互调控，以改善BMSCs的功能异常。
Abstract
Hydroquinone (HQ), a metabolite of benzene, is frequently utilized as a surrogate for benzene in in vitro studies and is associated with the development of acute myeloid leukemia (AML). In the hemotoxicity caused by benzene and HQ, cell apoptosis plays a key role. However, the molecular mechanisms underlying HQ are unknown. Studies have indicated that Suv39h1 is involved in regulating cell division and proliferation by regulating histone H3K9me3. Meanwhile, the Wnt/β-catenin signaling pathway also plays a significant role in cell proliferation and apoptosis. Therefore, this study was aimed at exploring the regulatory role of Suv39h1 and the Wnt/β-catenin signaling pathway in the effects of HQ on bone marrow mesenchymal stem cells (BMSCs), as well as its influence on cell proliferation and apoptosis. The results demonstrated that HQ elevated the levels of Suv39h1 and H3K9me3 and activated the Wnt/β-catenin signaling pathway by upregulating β-catenin, Wnt2b, C-myc, and Cyclin D1 and downregulating Wnt5a, resulting in an increase in cell growth and a decrease in apoptosis. Suv39h1 knockdown inhibited the Wnt/β-catenin signaling pathway. Meanwhile, inhibition of the Wnt/β-catenin signaling pathway resulted in the down-regulation of Suv39h1 and H3K9me3 in BMSCs. They both promoted cell proliferation and inhibited apoptosis in the effects of HQ on BMSCs by downregulating the expression of Cyt-C, Bax, Caspase 3, and Caspase 9 and upregulating the expression of Bcl-xl. Therefore, we concluded that Suv39h1 and the Wnt/β-catenin signaling pathway may mutually regulate each other in the effects of HQ on BMSCs in order to ameliorate the altered function of BMSCs.