Wen Lu, Chen Yan, Zeng Ling L, Zhao Fei, Yi Sha, Yang Li J, Zhang Ben P, Zhao Jie, Zhao Zi C, Zhang Chun
1277 Jiefang Avenue, Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, China.
Curr Pharm Biotechnol. 2015;17(2):147-60. doi: 10.2174/1389201016666150930115555.
As the principal active ingredient in the Chinese herb Tripterygium wilfordii Hook.F (TwHF), triptolide has been shown to have very strong antitumor properties. The trimethylation of lysine 4 on histone H3 (H3K4me3) has been proposed to promote gene expression, and the accumulation of H3K4me3 at the transcriptional start sites of oncogenes is involved in carcinogenesis. To identify the association between the reduction of H3K4me3 and the apoptosis of MM cells induced by triptolide, we investigated the global patterns of H3K4me3 occupancy in the MM cell genome. Combined analyses using ChIP-on-chip and western blotting showed that H3K4me3 were highly enriched on the gene promoters of c-Myc and VEGFA and were associated with the up-regulation of both genes. Treatment of KM3 cells with triptolide and siRNA targeting ASH2L reduced the expression of c-Myc and VEGFA. These results suggest that triptolide can down-regulate c-Myc and VEGFA expression by blocking the accumulation of H3K4me3 on their promoters,and thus play an important role in anti-MM mechanism.
雷公藤甲素作为中药雷公藤（Tripterygium wilfordii Hook.F, TwHF）中的主要活性成分，已被证明具有很强的抗肿瘤特性。组蛋白H3上赖氨酸4的三甲基化（H3K4me3）被认为可促进基因表达，癌基因转录起始位点处H3K4me3的积累参与致癌过程。为了确定H3K4me3的减少与雷公藤甲素诱导的骨髓瘤（MM）细胞凋亡之间的关联，我们研究了MM细胞基因组中H3K4me3占据的整体模式。芯片结合染色质免疫沉淀（ChIP-on-chip）和蛋白质免疫印迹分析表明，H3K4me3在c-Myc和VEGFA的基因启动子上高度富集，且与这两个基因的上调相关。用雷公藤甲素和靶向ASH2L的小干扰RNA（siRNA）处理KM3细胞可降低c-Myc和VEGFA的表达。这些结果表明，雷公藤甲素可通过阻止H3K4me3在其启动子上的积累来下调c-Myc和VEGFA的表达，从而在抗骨髓瘤机制中发挥重要作用。
