Acquired resistance and intrinsic to sorafenib therapy represents a major hurdle in improving the management of advanced hepatocellular carcinoma (HCC), which has been recently shown to be associated with the emergence of liver cancer stem cells (CSCs). However, it remains largely unknown whether and how histone posttranslational modifications, especially H3K27me3, are causally linked to the maintenance of self-renewal ability in sorafenib-resistant HCC. Here, we found that NOTCH1 signaling was activated in sorafenib-resistant HCC cells and NOTCH1 activation conferred hepatoma cells sorafenib resistance through enhanced self-renewal and tumorigenecity. Besides, the overexpression of EZH2 was required for the emergence of cancer stem cells following prolonged sorafenib treatment. As such, modulating EZH2 expression or activity suppressed activation of NOTCH1 pathway by elevating the expression of NOTCH1-related microRNAs, hsa-miR-21-5p and has-miR-26a-1-5p, via H3K27me3, and consequently weakened self-renewal ability and tumorigenecity and restored the anti-tumor effects of sorafenib. Overall, our results highlight the role of EZH2/NICD1 axis, and also suggest that EZH2 and NOTCH1 pathway are rational targets for therapeutic intervention in sorafenib-resistant HCC.

获得性耐药和索拉非尼疗法固有的特点是改善晚期肝细胞癌（HCC）管理的主要障碍，最近已证明这与肝癌干细胞（CSC）的出现有关。然而，仍然不清楚组蛋白的翻译后修饰，特别是H3K27me3，是否与维持索拉非尼耐药的HCC的自我更新能力有因果关系。在这里，我们发现NOTCH1信号在索拉非尼耐药HCC细胞中被激活，并且NOTCH1激活通过增强的自我更新和致瘤性赋予了肝癌细胞索拉非尼耐药性。此外，长时间的索拉非尼治疗后癌干细胞的出现需要EZH2的过表达。因此，通过H3K27me3，从而削弱了自我更新能力和致瘤性，并恢复了索拉非尼的抗肿瘤作用。总体而言，我们的结果突出了EZH2 / NICD1轴的作用，也表明EZH2和NOTCH1途径是索拉非尼耐药肝癌治疗干预的合理靶点。