Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma.
Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma.
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DOI：
10.1158/1535-7163.mct-17-0580
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发表时间：
2018-01
影响因子：
5.7
通讯作者：
Grembecka J
中科院分区：
文献类型：
--
作者：
Kempinska K;Malik B;Borkin D;Klossowski S;Shukla S;Miao H;Wang J;Cierpicki T;Grembecka J
肝细胞癌约占恶性肝脏肿瘤的85%，每年导致60万人死亡，强调了新疗法的必要性。据报道，肝细胞癌患者脑膜素水平升高，脑膜素水平高与患者预后不良有关。脑膜素和组蛋白甲基转移酶混合谱系白血病1(MLL1)之间的蛋白质-蛋白质相互作用在肝细胞癌的发生发展中起着重要作用，药物抑制这种相互作用可能为肝细胞癌患者提供新的治疗策略。在这里，我们证明了脑膜素-MLL抑制剂MI-503在体外和体内肝癌模型中显示出抗肿瘤活性，并揭示了脑膜素在肝癌中作用的潜在机制。MI-503治疗选择性地杀死各种肝癌细胞系，MI-503与索拉非尼的结合显著增强了这种效果，索拉非尼是治疗肝癌的标准护理疗法。此外，MI-503减少了体外肝癌模型中球体的形成和细胞的迁移。MI-503在体内应用时，无论是作为单一药物还是与索拉非尼联合应用，在小鼠肝细胞癌移植模型中都具有很强的抗肿瘤作用。从机制上讲，MI-503治疗下调了几个已知在肝癌细胞增殖和迁移中起关键作用的基因的表达，包括PEG10，并取代了PEG10启动子上的Menin-MLL1复合体，导致H3K4甲基化和转录抑制减少。总体而言，我们的研究揭示了脑膜素和肝细胞癌相关基因之间的机制联系，并表明药物抑制脑膜素-MLL相互作用可能是治疗肝细胞癌的一种有前途的方法。
Hepatocellular carcinoma (HCC) accounts for ~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 anti-tumor activity in in vitro and in vivo models of HCC and reveal 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 anti-tumor 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.