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

Abstract

Epigenetic modifiers often harbor loss-of-function mutations in lung cancer, but their tumorsuppressive 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 MLL4mutant lung cancer.

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

“…Our data also show selective sensitivity in mitochondrial oxidative phosphorylation deficient cancers driven by TCA cycle loss-of-function mutations as well as those “addicted” to glycolysis due to mutations in VHL 11 , 12 , 59 ( Extended Data Figure 7 ). Beyond these defined genomic populations with Enolase deficiencies, unique sensitivity to Enolase inhibition has also been documented in other genetic settings 60 , 61 testifying to greater utility of POMHEX and HEX. Thus, for the first time, we have provided in vivo proof-of-principle for the decisive efficacy of collateral lethality through pharmacological inhibition of Enolase.…”