Histone deacetylase inhibitor LMK-235-mediated HO-1 expression induces apoptosis in multiple myeloma cells via the JNK/AP-1 signaling pathway
Histone deacetylase inhibitor LMK-235-mediated HO-1 expression induces apoptosis in multiple myeloma cells via the JNK/AP-1 signaling pathway
复制标题
组蛋白脱乙酰酶抑制剂 LMK-235 介导的 HO-1 表达通过 JNK/AP-1 信号通路诱导多发性骨髓瘤细胞凋亡
DOI：
10.1016/j.lfs.2019.03.011
复制
发表时间：
2019-04-15
期刊：
影响因子：
6.1
通讯作者：
Wang, Jishi
中科院分区：
文献类型：
--
作者：
Li, Xinyao;Guo, Yongling;Wang, Jishi
目的：组蛋白去乙酰化酶抑制剂（HDACis）是一种很有前途的抗癌药物，为表观遗传药物的发现开辟了新的领域。多发性骨髓瘤（MM）是一种血液系统的恶性肿瘤，难以治愈且经常复发。本研究以MM细胞为研究对象，采用Real-time PCR和western blot方法检测HDAC 4和HO-1在LMK-235作用后MM细胞中的表达。使用si-RNA转染MM细胞。氯化血红素或ZnPP被组合以调节血红素加氧酶-1（HO-1），并且加入通路抑制剂以测量JNK/AP-1信号通路的变化。凋亡和增殖分别通过流式细胞术和CCK-8 assay.Key结果：我们发现，LMK-235，IIA类HDAC 4/5的选择性抑制剂，通过下调HO-1，这是密切相关的HDAC 4诱导MM细胞凋亡。LMK-235增加MM细胞中JNK和c-Jun的磷酸化。HO-1表达下调联合LMK-235表达进一步激活JNK和c-Jun的磷酸化并诱导MM细胞凋亡。当JNK抑制剂SP 600125联合使用时，凋亡现象被逆转。然而，当HO-1上调时，LMK-235介导的JNK和c-Jun磷酸化被抑制，MM细胞的凋亡开始减少。这为多发性骨髓瘤的治疗提供了新的思路。
Aims: Histone deacetylase inhibitors (HDACis) are promising anticancer drugs that open new areas of epigenetic drug discovery. Multiple myeloma (MM) is a malignant tumor of the blood system that is difficult to cure and often relapses. Here, we investigated the in vitro effects of a novel HDACi, LMK-235, on MM cells, and explored the underlying mechanisms.Main methods: Real-time PCR and western blot were used to measure the expression of HDAC4 and HO-1 in MM cells treated with LMK-235. si-RNA was used to transfect MM cells. Hemin or ZnPP was combined to regulate heme oxygenase-1 (HO-1), and a pathway inhibitor was added to measure changes in the JNK/AP-1 signaling pathway. Apoptosis and proliferation were assessed by flow cytometry and CCK-8 assay, respectively.Key findings: We found that LMK-235, a selective inhibitor of class IIA HDAC4/5, induced apoptosis of MM cells by downregulating HO-1 that is closely related to HDAC4. LMK-235 increased phosphorylation of JNK and c-Jun in MM cells. Downregulation of HO-1 expression in combination with LMK-235 expression further activated phosphorylation of JNK and c-Jun and induced apoptosis in MM cells. When the JNK inhibitor SP600125 was used in combination, the apoptosis phenomenon was reversed. However, when HO-1 was upregulated, LMK-235-mediated phosphorylation of JNK and c-Jun was inhibited, and apoptosis of MM cells began to decrease.Significance: These data suggest that LMK-235 has potent anti-myeloma activity through regulation of HO-1-induced apoptosis via the JNK/AP-1 pathway. This provides a new concept for the treatment of multiple myeloma.