ABSTRACT

Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a tumor suppressor that functions as an Mcl-1 E3 ligase to degrade Mcl-1 by ubiquitination. Here we discovered that treatment of various human lung cancer cells with DAC resulted in activation of FBW7 expression, decreased levels of Mcl-1 protein, and growth inhibition. DAC-activated FBW7 expression promoted Mcl-1 ubiquitination and degradation leading to a significant reduction in the half-life of Mcl-1 protein. Mechanistically, treatment of lung cancer cells or lung cancer xenografts with DAC induced the conversion of the FBW7 gene from a methylated form to an unmethylated form, which was associated with the increased expression of FBW7 and decreased expression of Mcl-1 in vitro and in vivo. DAC suppressed lung cancer growth in a dose-dependent manner in vivo. Combined treatment with DAC and a Bcl2 inhibitor, venetoclax, exhibited strong synergistic potency against lung cancer without normal tissue toxicity. These findings uncover a novel mechanism by which DAC suppresses tumor growth by targeting the FBW7/Mcl-1 signaling pathway. Combination of DAC with Bcl2 inhibitor venetoclax provides more effective epigenetic therapy for lung cancer.

摘要

甲基化诱导人肺癌中肿瘤抑制基因的表观遗传沉默。地西他滨 (DAC) 对 DNA 甲基转移酶的抑制可以使表观遗传沉默的肿瘤抑制基因去甲基化并激活。使用 DAC 的表观遗传治疗应该是肺癌治疗的一个有吸引力的策略。FBW7 是一种肿瘤抑制因子，可作为 Mcl-1 E3 连接酶通过泛素化降解 Mcl-1。在这里，我们发现用 DAC 处理各种人类肺癌细胞导致 FBW7 表达激活、Mcl-1 蛋白水平降低和生长抑制。DAC 激活的 FBW7 表达促进 Mcl-1 泛素化和降解，导致 Mcl-1 蛋白的半衰期显着缩短。从机制上讲，体外和体内。DAC在体内以剂量依赖性方式抑制肺癌生长。DAC 和 Bcl2 抑制剂 venetoclax 的联合治疗对肺癌表现出强大的协同作用，而没有正常组织毒性。这些发现揭示了 DAC 通过靶向 FBW7/Mcl-1 信号通路抑制肿瘤生长的新机制。DAC 与 Bcl2 抑制剂 venetoclax 的组合为肺癌提供更有效的表观遗传疗法。