Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.

中文翻译：

---

KMT2D 缺乏会损害超级增强剂以赋予肺癌的糖酵解脆弱性。

表观遗传修饰剂经常在肺癌中出现功能丧失突变，但它们的肿瘤抑制作用却没有得到很好的表征。组蛋白甲基转移酶 KMT2D（一种 COMPASS 样酶，也称为 MLL4）是肺癌中最高度灭活的表观遗传修饰剂之一。在这里，我们表明 Kmt2d 的肺特异性缺失促进了小鼠的肺肿瘤发生并上调了促肿瘤发生程序，包括糖酵解。糖酵解的药理学抑制优先阻碍具有 KMT2D 失活突变的人肺癌细胞的致瘤性。从机制上讲，Kmt2d 缺失会广泛损害超级增强子/增强子的表观基因组信号，包括昼夜节律抑制子 Per2 的超级增强子。Kmt2d 的缺失降低了调节多个糖酵解基因的 PER2 的表达。