Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of chronic liver disease and hepatocellular carcinoma, Xiamen University, Chengzhi building 110, Xiang'an South Road, Xiamen 361102, PR China.
Department of Basic Medical Sciences, Medical College, Xiamen University, Chengzhi building 110, Xiang'an South Road, Xiamen 361102, PR China; Fujian Provincial Key Laboratory of chronic liver disease and hepatocellular carcinoma, Xiamen University, Chengzhi building 110, Xiang'an South Road, Xiamen 361102, PR China.
Biochim Biophys Acta Gene Regul Mech. 2018 Feb;1861(2):117-124. doi: 10.1016/j.bbagrm.2017.12.007. Epub 2018 Feb 3.
The expression of insulin-like growth factor 2 (IGF2), a classical imprinting gene, didn't completely correlate with its imprinting profiles in hepatocellular carcinoma (HCC). The mechanistic importance of promoter activity in regulation of IGF2 has not been fully clarified. Here we show that histone 3 lysine 4 trimethylation (H3K4me3) modified by menin-MLL complex of IGF2 promoter contributes to promoter activity of IGF2. The strong binding of menin and abundant H3K4me3 at the DNA demethylated P3/4 promoters were observed in Hep3B cells with the robust expression of IGF2. In IGF2-low-expressing HepG2 cells, menin didn't bind to DNA hypermethylated P3/4 regions; however, menin overexpression inhibited DNA methylation and promoted H3K4me3 at the P3/4 as well as IGF2 expression in HepG2. In addition, the H3K4me3 at P3/4 locus was activated in primary HCC specimens with high IGF2 expression. Furthermore, inhibition of the menin/MLL interaction via MI-2/3 reduced IGF2 expression, inhibited the IGF1R-AKT pathway, and significantly repressed HCC with robust expression of IGF2. Taken together, we conclude that H3K4me3 of P3/4 locus mediated by the menin-MLL complex is a novel epigenetic mechanism for releasing IGF2.
胰岛素样生长因子 2（IGF2）的表达，作为一个经典的印迹基因，与肝癌（HCC）中的印迹模式并不完全相关。启动子活性在 IGF2 调控中的机制重要性尚未完全阐明。在这里，我们发现 IGF2 启动子的组蛋白 3 赖氨酸 4 三甲基化（H3K4me3）由 menin-MLL 复合物修饰，有助于 IGF2 启动子的活性。在 IGF2 表达强烈的 Hep3B 细胞中，观察到 menin 与 IGF2 启动子去甲基化的 P3/4 启动子有强烈的结合，并有丰富的 H3K4me3。在 IGF2 低表达的 HepG2 细胞中，menin 不与 DNA 高甲基化的 P3/4 区域结合；然而，menin 的过表达抑制了 DNA 甲基化，并促进了 P3/4 处的 H3K4me3 和 IGF2 在 HepG2 中的表达。此外，在 IGF2 表达较高的原发性 HCC 标本中，P3/4 位点的 H3K4me3 被激活。此外，通过 MI-2/3 抑制 menin/MLL 相互作用，降低 IGF2 表达，抑制 IGF1R-AKT 通路，显著抑制 IGF2 表达强烈的 HCC。综上所述，我们得出结论，P3/4 位点的 H3K4me3 由 menin-MLL 复合物介导，是一种释放 IGF2 的新型表观遗传机制。
