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

Mayinuer Maitituoheti, Emily Z. Keung, Ming Tang, Liang Yan, Hunain Alam, Guangchun Han, Anand K. Singh, Ayush T. Raman, Christopher Terranova, Sharmistha Sarkar, Elias Orouji, Samir B. Amin, Sneha Sharma, Maura Williams, Neha S. Samant, Mayura Dhamdhere, Norman Zheng, Tara Shah, Amiksha Shah, Jacob B. AxelradNazanin E. Anvar, Yu Hsi Lin, Shan Jiang, Edward Q. Chang, Davis R. Ingram, Wei Lien Wang, Alexander Lazar, Min Gyu Lee, Florian Muller, Linghua Wang, Haoqiang Ying, Kunal Rai

    Research output: Contribution to journalArticlepeer-review

    35 Scopus citations


    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.

    Original languageEnglish (US)
    Article number108293
    JournalCell Reports
    Issue number3
    StatePublished - Oct 20 2020


    • 2-DG
    • IGFBP5
    • KMT2D
    • Linsitinib
    • RNAi screen
    • chromatin
    • epigenetics
    • glycolysis
    • melanoma
    • mouse model

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)


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