KMT2D缺失削弱增強子賦予肺癌糖酵解易感性的能力
作者：
小柯機器人發布時間：2020/4/7 14:27:30
美國德克薩斯大學MD安德森癌症中心Min Gyu Lee和Kunal Rai合作有了新發現。他們揭示KMT2D缺失削弱增強子賦予肺癌糖酵解易感性的能力。相關論文於2020年4月2日發表在《癌細胞》雜誌上。
據悉，表觀遺傳修飾子經常在肺癌中具有功能喪失突變，但其腫瘤抑制作用的特徵較差。組蛋白甲基轉移酶KMT2D（一種COMPASS類酶，也稱為MLL4）是肺癌中最高度失活的表觀遺傳修飾子之一。
他們表明，KMT2D的肺特異性丟失促進了小鼠的肺腫瘤發生，並上調了促腫瘤發生程序，包括糖酵解。糖酵解的藥理學抑制作用優先阻止攜帶KMT2D失活突變的人肺癌細胞的致瘤性。
從機理上講，KMT2D缺失會大大削弱超級增強子/增強子的表觀基因組信號，包括晝夜節律抑制器Per2的超級增強子。KMT2D的丟失會降低PER2的表達，從而調節多個糖酵解基因。這些發現表明，KMT2D是一種肺部腫瘤抑制因子，而KMT2D缺乏導致糖酵解抑制劑治療上的易感性。
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