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Alam, Hunain; Tang, Ming; Maitituoheti, Mayinuer; Dhar, Shilpa S.; Kumar, Manish; Han, Chae Young; Ambati, Chandrashekar R.; Amin, Samir B.; Gu, Bingnan; Chen, Tsai-Yu; Lin, Yu-Hsi; Chen, Jichao; Muller, Florian L.; Putluri, Nagireddy; Flores, Elsa R.; DeMayo, Francesco J.; Baseler, Laura; Rai, Kunal; Lee, Min Gyu
Cancer cell, 04/2020, Letnik: 37, Številka: 4Journal Article
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. Display omitted •Lung-specific Kmt2d loss in mice promotes lung tumorigenesis•Kmt2d loss impairs enhancers, including a super-enhancer for the tumor suppressor Per2•KMT2D activates Per2 expression and thereby represses glycolytic genes•Glycolysis inhibition impedes the growth of KMT2D-mutant lung cancer Histone methyltransferase KMT2D is frequently mutated in lung tumors, and Alam et al. identify KMT2D as a lung tumor suppressor. KMT2D deficiency induces aberrant metabolic reprogramming via super-enhancer impairment, conferring sensitivity to glycolytic inhibitors in lung cancer with KMT2D-inactivating mutations.
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