Global gene expression profiling of K-RasLSL-G12D and K-RasLSL-G12D;Mll4fl/fl lung tumors using RNA sequencing

Here, we show that the histone H3 lysine (H3K4) methyltransferase MLL4 (a COMPASS/SET1-like enzyme; also called KMT2D) is ranked the most highly inactivated epigenetic modifier in NSCLC tumors lung-specific loss of Mll4 accelerates K-RasG12D-induced lung tumorigenesis in mice while reducing their survival time. Mll4 loss upregulated tumor-promoting programs, such as glycolysis, which is also enriched in human lung tumors with low MLL4 levels or MLL4 inactivation. The inhibition of glycolysis selectively impeded the proliferation and tumorigenic growth of NSCLC cells bearing human MLL4-inactivating mutation. Mll4 loss caused widespread impairment of super-enhancer signals, including super-enhancer associated with the circadian transcriptional repressor gene Per2 which represses glycolysis genes in NSCLC cells. Overall design: K-RasLSL-G12D and K-RasLSL-G12D;Mll4fl/fl lung tumor