Hepatocellular carcinoma (HCC) accounts for approximately 85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein–protein interaction between menin and histone methyltransferase mixed lineage leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin–MLL inhibitor MI-503 shows antitumor activity in in vitro and in vivo models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin–MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin–MLL interaction might represent a promising therapeutic approach for HCC. Mol Cancer Ther; 17(1); 26–38. ©2017 AACR.

中文翻译：

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对menin-MLL相互作用的药理学抑制导致PEG10的转录抑制并阻断肝细胞癌

肝细胞癌 (HCC) 约占肝脏恶性肿瘤的 85%，每年导致 600,000 人死亡，这强调了对新疗法的需求。据报道，HCC 患者中menin 上调，高水平menin 与患者预后不良相关。Menin 和组蛋白甲基转移酶混合谱系白血病 1 (MLL1) 之间的蛋白质-蛋白质相互作用在 HCC 的发展中起着重要作用，这意味着对这种相互作用的药理学抑制可能会为 HCC 患者带来新的治疗策略。在这里，我们证明了menin-MLL抑制剂MI-503在HCC的体外和体内模型中显示出抗肿瘤活性，并揭示了menin对HCC的贡献的潜在机制。MI-503 治疗选择性地杀死各种 HCC 细胞系，并且 MI-503 与索拉非尼（HCC 的标准护理疗法）的组合显着增强了这种效果。此外，MI-503 在体外 HCC 模型中减少球体形成和细胞迁移。当在体内应用时，MI-503 作为单一药物和与索拉非尼组合在 HCC 小鼠异种移植模型中都具有很强的抗肿瘤作用。从机制上讲，用 MI-503 治疗会下调已知在 HCC 细胞增殖和迁移中起关键作用的几种基因的表达，包括 PEG10，并从 PEG10 启动子上取代 menin-MLL1 复合物，导致 H3K4 甲基化减少和转录抑制。全面的，我们的研究揭示了menin和HCC相关基因之间的机制联系，并证明menin-MLL相互作用的药理学抑制可能代表了一种有前途的HCC治疗方法。摩尔癌症治疗; 17(1); 26-38。©2017 AACR。