姜黄素通过抑制 EZH2 对骨髓增生异常综合征的抗癌作用。

Anti-cancer Effects of Curcumin on Myelodysplastic Syndrome through the Inhibition of Enhancer of Zeste Homolog-2 (EZH2).

机构信息

Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

出版信息

Curr Cancer Drug Targets. 2019;19(9):729-741. doi: 10.2174/1568009619666190212121735.

DOI:10.2174/1568009619666190212121735

PMID:30747066

Abstract

BACKGROUND

Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase that regulates histone H3 methylation of lysine27 (H3K27me3), is involved in the pathogenesis of myelodysplastic syndrome (MDS). Targeting epigenetic regulators has been identified as a potential treatment target in MDS chemotherapy. Curcumin, a natural compound extracted from turmeric, was found to possess a wide range of anticancer activities in various tumors.

METHODS

This study was designed to investigate the inhibitory effect and action mechanism of curcumin in myelodysplastic syndrome (MDS) in vitro and in vivo.

RESULTS

Our results showed that curcumin can significantly suppress cell proliferation and induce cell apoptosis and cell cycle arrest in human MDS-derived cell lines. It reduced EZH2, DNA methyltransferase 3A (DNMT3a), ASXL1 and downstream H3K4me3, H3K27me3 and HOXA9 expression and inhibited EZH2 and H3K27me3 nuclear translocation. Curcumin also showed anti-cancer effects in a xenograft mouse model and reduced EZH2, H3K4me3 and H3K27me3 in vivo. EZH2 knockdown can reduce the H3K27me3 levels and induce curcumin resistance in vitro but attenuates leukemic transformation in vivo.

CONCLUSION

These findings provide the potential molecular mechanism of curcumin as a therapeutic agent for MDS.

摘要

背景

EZH2（增强子结合锌指蛋白 2）是一种组蛋白甲基转移酶，可调节赖氨酸 27 位的组蛋白 H3 甲基化（H3K27me3），参与骨髓增生异常综合征（MDS）的发病机制。靶向表观遗传调节剂已被确定为 MDS 化疗的潜在治疗靶点。姜黄素是从姜黄中提取的天然化合物，在多种肿瘤中被发现具有广泛的抗癌活性。

方法

本研究旨在体外和体内研究姜黄素对骨髓增生异常综合征（MDS）的抑制作用及其作用机制。

结果

我们的结果表明，姜黄素可显著抑制人 MDS 细胞系的细胞增殖，并诱导细胞凋亡和细胞周期停滞。它降低了 EZH2、DNA 甲基转移酶 3A（DNMT3a）、ASXL1 以及下游的 H3K4me3、H3K27me3 和 HOXA9 的表达，并抑制了 EZH2 和 H3K27me3 的核转位。姜黄素在异种移植小鼠模型中也显示出抗癌作用，并降低了体内的 EZH2、H3K4me3 和 H3K27me3。EZH2 敲低可降低 H3K27me3 水平并在体外诱导姜黄素耐药，但可减弱体内白血病转化。