美国德克萨斯大学MD安德森癌症中心Min Gyu Lee和Kunal Rai合作有了新发现。他们揭示KMT2D缺失削弱增强子赋予肺癌糖酵解易感性的能力。相关论文于2020年4月2日发表在《癌细胞》杂志上。

据悉，表观遗传修饰子经常在肺癌中具有功能丧失突变，但其肿瘤抑制作用的特征较差。组蛋白甲基转移酶KMT2D（一种COMPASS类酶，也称为MLL4）是肺癌中最高度失活的表观遗传修饰子之一。

他们表明，KMT2D的肺特异性丢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作用优先阻止携带KMT2D失活突变的人肺癌细胞的致瘤性。

从机理上讲，KMT2D缺失会大大削弱超级增强子/增强子的表观基因组信号，包括昼夜节律抑制器Per2的超级增强子。KMT2D的丢失会降低PER2的表达，从而调节多个糖酵解基因。这些发现表明，KMT2D是一种肺部肿瘤抑制因子，而KMT2D缺乏导致糖酵解抑制剂治疗上的易感性。

附：英文原文

Title: KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

Author: Hunain Alam, Ming Tang, Mayinuer Maitituoheti, Shilpa S. Dhar, Manish Kumar, Chae Young Han, Chandrashekar R. Ambati, Samir B. Amin, Bingnan Gu, Tsai-Yu Chen, Yu-Hsi Lin, Jichao Chen, Florian L. Muller, Nagireddy Putluri, Elsa R. Flores, Francesco J. DeMayo, Laura Baseler, Kunal Rai, Min Gyu Lee

Issue&Volume: 2020-04-02

Abstract: Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer,but their tumor-suppressive roles are poorly characterized. Histone methyltransferaseKMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivatedepigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, includingglycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicityof human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically,Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including thesuper-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findingsindicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers atherapeutic vulnerability to glycolytic inhibitors.

DOI: 10.1016/j.ccell.2020.03.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30106-9