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Super-enhancer impairment is a link between MLL4 inactivated lung tumors and their vulnerability to glycolysis pathway inhibition

By Hunain Alam, Ming Tang, Mayinuer Maitituoheti, Shilpa S. Dhar, Samir Amin, Bingnan Gu, Tsai-Yu Chen, Yu-His Lin, Jichao Chen, Florian Muller, Francesco J. DeMayo, Laura Baseler, Kunal Rai, Min Gyu Lee

Posted 28 Dec 2018
bioRxiv DOI: 10.1101/507202

Epigenetic modifiers often harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Here we show that lung-specific loss of the gene encoding the histone methyltransferase MLL4 (alias KMT2D; a COMPASS-like enzyme), which is ranked the most highly inactivated epigenetic modifier in lung cancer, strongly promotes lung adenocarcinoma in mice. Mll4 loss upregulated tumor-promoting programs, including glycolysis. The pharmacological inhibition of glycolysis preferentially impeded tumorigenic growth of human lung cancer cells bearing MLL4-inactivating mutations. Mll4 loss widely impaired epigenomic signals for super-enhancers and enhancers, including the super-enhancer for the circadian rhythm repressor gene Per2, and decreased Per2 expression. Per2 downregulated several glycolytic pathway genes. These findings uncover a distinct tumor-suppressive epigenetic mechanism in which MLL4 enhances Per2-mediated repression of pro-tumorigenic glycolytic genes via super-enhancer activation to suppress lung adenocarcinoma tumorigenesis and also implicate a glycolysis-targeting strategy as a therapeutic intervention for the treatment of MLL4-mutant lung cancer.

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