20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription
20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription
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DOI：
10.1016/j.ejphar.2017.09.023
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发表时间：
2017-11-15
影响因子：
5
通讯作者：
Li, Qi
中科院分区：
文献类型：
--
作者：
Li, Qi;Li, Bai;Li, Qi
20(S)-人参皂苷Rh2(20(S)-GrA2)在控制人肝细胞癌方面具有重要的药理作用。EZH2是H3K27me3的组蛋白甲基转移酶，H3K27me3在许多恶性肿瘤中被确定为癌基因。CDKN2A-2B基因簇编码三种重要的肿瘤抑制基因P14、P15和P16。本研究探讨了20(S)GRh2对人肝癌的抗癌作用及其分子机制。20(S)-GRh2可抑制肝癌细胞的增殖、迁移，并诱导细胞周期停滞于G0/G1期，抑制体内肿瘤生长。我们首次证明了这种效应是通过下调EZH2的表达而特异性地介导的。进一步的分子机制研究表明，降低的EZH2通过减少CDKN2A-2B基因簇基因启动子上的H3K27me3修饰来促进P14、P15和P16基因的转录。同样，siRNA沉默EZH2可下调P14、P15、P16的mRNA水平，抑制肝癌细胞的增殖。我们的结果表明，EZH2可能是20(S)-GRh2治疗肝癌的潜在靶点，这为开发抑制组蛋白甲基酶的药物作为抗多种癌症的策略提供了理论基础。
20(S)-Ginsenoside Rh2 (20(S)-GRh2) exerts important pharmacological effects with regard to the control of human hepatocellular carcinoma (HCC). EZH2 is a potent histone methyltransferase of H3K27me3, which has been determined as an oncogene in many malignancies. The CDKN2A-2B gene cluster encodes three important tumor suppressors, P14, P15 and P16. In this study, the anticancer effect and molecular mechanism of 20(S)GRh2 on HCC was investigated. Treatment of HCC cells with 20(S)-GRh2 inhibited cell proliferation, migration and induced cell cycle arrest at the G0/G1 phase, and inhibited tumor growth in vivo. We demonstrate for the first time that this effect was specifically mediated by down-regulating expression of EZH2. Further molecular mechanism study indicated that the decreased EZH2 promoted P14, P15 and P16 gene transcription through reducing H3K27me3 modification in the promoter of CDKN2A-2B gene cluster loci. Similarly, silencing of EZH2 by siRNA down-regulated P14, P15, P16 mRNA levels and inhibited HCC cell proliferation. Our results suggested that EZH2 could be a potentially therapeutic target by 20(S)-GRh2 in HCC, which provided a rationale for the development of drugs that inhibited histone methylase as a strategy against various cancers.