KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer

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 growth 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 KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors. Significance Lung cancer is the leading cause of cancer deaths. The overall survival rate for lung cancer patients remains low despite recent therapeutic advances, and a majority of lung cancer patients lack a druggable target. Therefore, there is a great need for a better understanding of the molecular mechanisms driving lung cancer. Epigenetic modifiers are frequently lost in lung cancer, but how this provokes lung tumorigenesis remains unclear. We show that KMT2D, which is recurrently mutated in lung cancer, is a lung tumor suppressor. Our results uncover a tumor-promoting epigenetic mechanism by which KMT2D-inactivating mutations induce aberrant metabolic reprogramming via super-enhancer impairment in lung cancer. Our findings support a glycolysis-inhibitory approach as a therapeutic intervention strategy against KMT2D-mutant lung cancer.