Together, these data suggest that upregulated glycolysis is an important contributor to enhanced tumorigenesis in KMTD mutant melanomas and suggest a potential therapeutic strategy in this genetic context.These lost active enhancer peaks were associated with important melanoma regulatory genes in immune pathways, apoptosis signaling pathway, and p pathway by glucose deprivation. These data suggest that KMTD loss results in signicant reprogramming of the enhancer landscape in melanoma.Of the, active enhancer loci that display a loss of intensity in KMTD mutant tumors compared with WT, were located nearby. These genes were enriched for those involved in various phosphorylationmediated cell signaling events and are bona de or putative tumor suppressors. However, in contrast to observations in pancreatic cancer, we observed reduced levels of the phosphorylated form of mTOR in KMTD mutant versus WT cells in the CCLE database RPPA data. The functional signicance of activation of IGFR signaling was further tested by the treatment of cells with an IGFR inhibitor, which reduced the expression of glycolysis genes in KMTD mutant murine and human cell lines. Importantly, treatment of KMTD mutant murine and human cell lines with linsitinib preferentially reduced the proliferation of KMTD mutant cell lines both in vitro. This nding was recapitulated in the analysis of all cancer cell lines for which linsitinib sensitivity data were available.Cells harboring KMTD functional driver mutations displayed signicantly lower IC values for linsitinib treatment than for cells that harbor high levels of KMTD. We focused on IGFBP as it is a known negative regulator of IGFR signaling and acts as a tumor suppressor in melanoma by regulation of AKT and IGFR signaling. Consistently, IGFBP expression was also lost in KMTD mutant murine and human cell lines. Consistently, IGFBP expression was signicantly reduced in KMTD mutant human and murine melanoma tumors. Consistently, we also noted a positive correlation between IGFBP expression and KMTD expression in the metastatic tumors in the TCGA melanoma study. We also did not observe any change in TSC expression in KMTD mutant versus WT cell lines led to an increased expression of glycolysis enzymes. Importantly, epistasis experiments revealed that IGFBP overexpression in murine melanoma cells decreased levels of IGFR and AKT phosphorylation in KMTD mutant murine and human cells compared with their WT counterparts.Taken together, the data presented in this manuscript establish a model of KMTD function in cancer for which KMTD acts as a tumor suppressor by enhancer reprogramming on tumor suppressor genes, such as IGFBP, that regulate key pathways, such as IGFR signaling, leading to metabolic rewiring. The bottom and the top rectangles indicate the rst quartile, and the vertical lines that extend from the top and the bottom of the plot indicate the maximum and minimum values, respectively.Each row represents one chromatin state, and each column corresponds to one chromatin mark.Color intensities represent the relative fold enrichment.Enhancers are shown in a kb window centered on the middle of the enhancer in iBIP;KMTD and iBIP;KMTDLL melanoma tumors.Interestingly we identied four enzymes regulating HK methylation, namely, KMTD, and KDMA, as hits in this screen, suggesting important roles for HK methylation reprogramming during tumorigenesis.