Journal
CANCER CELL
Volume 37, Issue 4, Pages 599-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.03.005
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Funding
- National Institutes of Health (NIH) [R01CA157919, R01CA207109, R01CA207098]
- Center for Cancer Epigenetics (Solexa allowance) at the MD Anderson Cancer Center
- NIH [R01CA216426, R01CA220297, R00CA160578, R35CA197452]
- American Cancer Society [127430-RSG-15-105-01-CNE, RSG-15-145-01-CDD]
- National Institute of Environmental Health Sciences [Z1AES103311-10]
- Cancer Prevention and Research Institute of Texas [RP170005]
- NIH National Cancer Institute [P30CA016672]
- Center for Cancer Epigenetics at the MD Anderson Cancer Center
- Odyssey program at the MD Anderson Cancer Center
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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.
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