Department of Blood Transfusion, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
Department of Hematology, Southern University of Science and Technology Hospital, Shenzhen, China.
Invest New Drugs. 2021 Aug;39(4):961-970. doi: 10.1007/s10637-021-01079-5. Epub 2021 Feb 10.
Our previous studies revealed that MYCN downregulates the expression of DKK3, activates the Wnt/β-catenin signalling pathway at the transcriptional level, and thereby promotes the development of B cell acute lymphocytic leukaemia (B-ALL) but does not affect the methylation of the DKK3 promoter. Some studies have shown that MYCN is associated with histone acetylation. We speculate that histone deacetylase inhibitors (HDACis) can inhibit the Wnt/β-catenin signalling pathway by inhibiting MYCN and increasing the expression of DKK3. Based on previous experiments, we tested this hypothesis by analysing the changes in MYCN, DKK3 and the Wnt/β-catenin signalling pathways in B-ALL cells after treatment with the selective HDACi chidamide. The in vitro and in vivo experiments confirmed that chidamide inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of histone deacetylase, and these effects resulted in inhibition of the Wnt/β-catenin signalling pathway and the proliferation of B-ALL cells. These findings indicate that chidamide might be used alone or in combination with other chemotherapy regimens for patients with B-ALL and thus provide a new approach to the treatment of B-ALL.
我们之前的研究表明，MYCN 下调 DKK3 的表达，在转录水平激活 Wnt/β-catenin 信号通路，从而促进 B 细胞急性淋巴细胞白血病（B-ALL）的发展，但不影响 DKK3 启动子的甲基化。一些研究表明，MYCN 与组蛋白乙酰化有关。我们推测组蛋白去乙酰化酶抑制剂（HDACi）可以通过抑制 MYCN 和增加 DKK3 的表达来抑制 Wnt/β-catenin 信号通路。基于之前的实验，我们通过分析选择性 HDACi 西达本胺处理后 B-ALL 细胞中 MYCN、DKK3 和 Wnt/β-catenin 信号通路的变化来检验这一假设。体外和体内实验证实，西达本胺通过抑制组蛋白去乙酰化酶的活性抑制 MYCN 的表达并增加 DKK3 的表达，这些作用导致 Wnt/β-catenin 信号通路的抑制和 B-ALL 细胞的增殖。这些发现表明，西达本胺可能单独或与其他化疗方案联合用于治疗 B-ALL 患者，从而为治疗 B-ALL 提供了一种新方法。
