Guizhou Medical University, Guiyang, Guizhou, China; Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China; Guizhou Province Laboratory of Haematopoietic Stem Cell Transplantation Center, Guiyang, Guizhou, China.
Linyi Central Hospital, Linyi, Shandong, China.
Life Sci. 2019 Apr 15;223:146-157. doi: 10.1016/j.lfs.2019.03.011. Epub 2019 Mar 12.
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.
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.
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.
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.
组蛋白去乙酰化酶抑制剂（HDACi）是一种很有前途的抗癌药物，为表观遗传药物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，难以治愈且常复发。本研究旨在探讨新型 HDACi LMK-235 对 MM 细胞的体外作用，并探索其潜在机制。
实时 PCR 和 Western blot 用于检测 LMK-235 处理的 MM 细胞中 HDAC4 和 HO-1 的表达。siRNA 转染 MM 细胞。血红素或 ZnPP 联合调节血红素加氧酶-1（HO-1），并加入通路抑制剂以测量 JNK/AP-1 信号通路的变化。通过流式细胞术和 CCK-8 测定分别评估细胞凋亡和增殖。
我们发现，选择性抑制 IIA 类 HDAC4/5 的 LMK-235 通过下调与 HDAC4 密切相关的 HO-1 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 表达下调与 LMK-235 表达联合进一步激活 JNK 和 c-Jun 的磷酸化，并诱导 MM 细胞凋亡。当使用 JNK 抑制剂 SP600125 联合时，凋亡现象被逆转。然而，当 HO-1 上调时，LMK-235 介导的 JNK 和 c-Jun 的磷酸化被抑制，MM 细胞的凋亡开始减少。
这些数据表明，LMK-235 通过调节 HO-1 诱导的 JNK/AP-1 通路介导的细胞凋亡对多发性骨髓瘤具有强大的抗骨髓瘤活性。这为多发性骨髓瘤的治疗提供了新的概念。
