HeterozygousKmt2dloss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation

Abstract

SUMMARYThe histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and many other types of cancer. Notably, heterozygous loss ofKMT2Dis prevalent in MB and other cancer types. However, what role heterozygousKMT2Dloss plays in tumorigenesis has not been well characterized. Here, we show that heterozygousKmt2dloss highly promotes MB driven by heterozygous loss of the MB suppressor genePtchin mice. HeterozygousKmt2dloss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, inPtch+/−-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygousKmt2dloss and upregulation of the oncogeneMycNby heterozygousPtchloss increased the expression of tumor-promoting genes. Moreover, heterozygousKmt2dloss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g.,Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the enhancer-decommissioning H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygousKmt2dloss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygousKMT2Dloss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygousKMT2Dloss.