Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1901 East Road, Houston, TX 77054, USA.
Cancer Cell. 2020 Apr 13;37(4):599-617.e7. doi: 10.1016/j.ccell.2020.03.005. Epub 2020 Apr 2.
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.
表观遗传修饰因子在肺癌中经常发生功能丧失突变，但它们的肿瘤抑制作用尚未得到充分表征。组蛋白甲基转移酶 KMT2D（一种类似 COMPASS 的酶，也称为 MLL4）是肺癌中失活程度最高的表观遗传修饰因子之一。在这里，我们表明，肺特异性的 Kmt2d 缺失会促进小鼠的肺癌发生，并上调促肿瘤发生程序，包括糖酵解。糖酵解的药理学抑制优先阻碍携带 KMT2D 失活突变的人肺癌细胞的致瘤性。从机制上讲，Kmt2d 缺失广泛损害了超级增强子/增强子的表观基因组信号，包括昼夜节律抑制剂 Per2 的超级增强子。Kmt2d 的缺失会降低 PER2 的表达，PER2 调节多种糖酵解基因。这些发现表明 KMT2D 是一种肺肿瘤抑制因子，KMT2D 缺失赋予对糖酵解抑制剂的治疗脆弱性。
