Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokenadai, Minato-ku, Tokyo, 108-8639, Japan.
Sci Rep. 2021 Nov 1;11(1):21396. doi: 10.1038/s41598-021-00889-0.
Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2H3K27me3 cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
EZH2 和其同源物 EZH1 均作为组蛋白 H3 赖氨酸 27（H3K27）甲基转移酶发挥作用，并抑制靶基因的转录。H3K27 三甲基化（H3K27me3）的失调在肝癌（HCC）等癌症的发展和进展中起着重要作用。本研究调查了 EZH1/2 的表达与 HCC 中 H3K27me3 水平之间的关系。此外，还分析了 EZH1/2 在细胞生长、致瘤性和索拉非尼耐药中的作用。与 EZH1 或 EZH2 单敲低相比，慢病毒敲低和 EZH1/2 的药理学抑制（UNC1999）均降低了 H3K27me3 水平并抑制了肝癌细胞的生长。尽管在 HCC 样本中观察到 EZH2 表达与 H3K27me3 水平之间存在显著相关性，但 EZH1 的过表达似乎导致一些 EZH2H3K27me3 病例中 H3K27me3 水平升高。索拉非尼治疗后 Akt 抑制通过降低 EZH2 丝氨酸 21 的磷酸化导致 H3K27me3 水平增加。索拉非尼和 UNC1999 的联合使用在体外和体内均表现出协同的抗肿瘤作用。联合治疗取消了索拉非尼诱导的 H3K27me3 水平升高，表明 EZH2 功能的激活是 HCC 索拉非尼耐药的机制之一。总之，索拉非尼加 EZH1/2 抑制剂可能成为 HCC 的一种新的治疗方法。
