Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma

Abstract

SUMMARY Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

Cancer-epigenetic function of the histone methyltransferase KMT2D and therapeutic opportunities for the treatment of KMT2D-deficient tumors

“…In patient-derived xenograft (PDX) melanoma models, KMT2D was required for the growth and invasion of N-RAS-mutated melanoma and positively regulated genes for tumor growth and cell migration [45]. This finding appears to be in disagreement with the above-described melanoma study by Maitituoheti et al [33], which showed a tumor-suppressive role for KMT2D. Dawkins et al [46] reported that high KMT2D levels correlated with worse prognosis in patients with pancreatic cancer and that KMT2D positively regulated cell cycle genes in several pancreatic cancer cell lines.…”

“…We have also shown that expression of the circadian transcription-repressive tumor suppressor Per2 is positively regulated by a KMT2D-activated, tumor-suppressive super-enhancer to attenuate lung tumorigenesis [32]. Moreover, KMT2D positively regulates the enhancer of the tumor suppressor gene IGFBP5 for melanoma suppression [33] and the enhancers of several tumor suppressor genes (e.g., Socs3, Asxl1 and Arid1A) for lymphoma suppression [35]. Therefore, KMT2D plays a critical role in activating tumor-suppressive enhancers and super-enhancers.…”

“…These microenvironments may involve intact immune systems that would better support the growth of KMT2D-deficient tumors than that of KMT2D-wild type (WT) tumors. Supporting this point, it was shown that KMT2D-deficient syngeneic tumors were more sensitive to immunotherapy than were KMT2D-WT tumors [49] and that immune response pathways were more enriched in KMT2D-deficient melanoma than in KMT2D-WT melanoma [33].…”

“…Interestingly, KMT2D activates expression of the tumor suppressor Per2 and thereby downregulates expression of tumor-promoting glycolytic genes in K-Ras G12D -driven lung tumors [32]. Similarly, Maitituoheti et al [33] showed that Kmt2d loss promoted melanoma in a GEMM and that KMT2D downregulated expression of glycolytic genes by increasing expression of IGFBP5, a tumor suppressor and negative regulator of IGF1R signaling. In a study of pancreatic cancer, Koutsioumpa et al [34] showed that KMT2D levels were downregulated in pancreatic tumors compared to normal pancreatic tissues and that KMT2D decreased glycolysis via downregulation of the glucose transporter SLC2A3 (alias GLUT3) to suppress tumorigenicity of pancreatic cancer cell lines.…”

“…Consistent with our finding that Kmt2d loss increases glycolysis in lung tumorigenesis, [32], we showed that pharmacological inhibition of glycolysis using 2-deoxy-D-glucose impeded the proliferation of human lung cancer cell lines bearing KMT2D truncations to a greater extent than that of KMT2D-WT lung cancer cell lines and selectively inhibited the tumorigenicity of KMT2D-deficient lung cancer cells in mice [32]. Similarly, pharmacological inhibition of the glycolysis pathway using 2-deoxy-D-glucose, POMHEX (an enolase1 inhibitor), and lonidamine (a hexokinase inhibitor) selectively impeded the proliferation of KMT2D-mutant melanoma cells compared with that of KMT2D WT melanoma cells [33]. However, the OXPHOS inhibitor IACS-010759 did not have a significant selective inhibitory effect on the proliferation of KMT2D-deficient cancer cells compared to that of KMT2D-WT cancer cells [32,33].…”