KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer
KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer
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DOI：
10.1016/j.ccell.2020.03.005
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发表时间：
2020-04-13
期刊：
影响因子：
50.3
通讯作者：
Lee, Min Gyu
中科院分区：
文献类型：
--
作者：
Alam, Hunain;Tang, Ming;Lee, Min Gyu
表观遗传修饰因子在肺癌中经常携带功能丧失突变，但其肿瘤抑制作用的特征很差。组蛋白甲基转移酶KMT 2D（COMPASS样酶，也称为MLL 4）是肺癌中最高度失活的表观遗传修饰物之一。在这里，我们表明，肺特异性Kmt 2d的损失促进小鼠肺肿瘤的发生，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KMT 2D失活突变的人肺癌细胞的致瘤性。从机制上讲，Kmt 2d损失广泛损害了超级增强子/增强子的表观基因组信号，包括昼夜节律阻遏物Per 2的超级增强子。Kmt 2d的缺失降低了PER 2的表达，PER 2调节多种糖酵解基因。这些发现表明，KMT 2D是一种肺肿瘤抑制因子，KMT 2D缺陷赋予糖酵解抑制剂的治疗脆弱性。
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.