Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma
| Autor: | Ayush T. Raman, Ming Tang, Liang Yan, Emily Z. Keung, Guangchun Han, Maura Williams, Linghua Wang, Florian L. Muller, Wei Lien Wang, Amiksha Shah, Norman Zheng, Hunain Alam, Min Gyu Lee, Yu Hsi Lin, Christopher Terranova, Davis R. Ingram, Haoqiang Ying, Edward Q. Chang, Tara Shah, Shan Jiang, Samir B. Amin, Alexander J. Lazar, Elias Orouji, Mayinuer Maitituoheti, Jacob B. Axelrad, Kunal Rai, Nazanin Esmaeili Anvar, Mayura Dhamdhere, Sharmistha Sarkar, Sneha Sharma, Anand K Singh, Neha S. Samant |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Regulatory Sequences Nucleic Acid medicine.disease_cause Receptor IGF Type 1 Mice 0302 clinical medicine Insulin Genes Tumor Suppressor Glycolysis 050207 economics lcsh:QH301-705.5 RNAi screen 0303 health sciences 050208 finance 05 social sciences KMT2D Neoplasm Proteins Chromatin Cell biology DNA-Binding Proteins 030220 oncology & carcinogenesis Histone methyltransferase Histone Methyltransferases Intercellular Signaling Peptides and Proteins Female Reprogramming Myeloid-Lymphoid Leukemia Protein Signal Transduction Mice Nude Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor 0502 economics and business melanoma medicine Animals Humans Epigenetics Enhancer 030304 developmental biology epigenetics Histone-Lysine N-Methyltransferase Xenograft Model Antitumor Assays Mice Inbred C57BL Metabolic pathway Glucose 030104 developmental biology lcsh:Biology (General) Tumor progression chromatin IGFBP5 Carrier Proteins Carcinogenesis 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 33, Iss 3, Pp 108293-(2020) Cell reports |
| DOI: | 10.1101/507327 |
| Popis: | 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. In Brief Through an in vivo epigenome-focused pooled RNAi screen, Maitituoheti et al. identify KMT2D as a tumor suppressor in melanoma. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways by reduction of H3K4me1-marked active enhancers, conferring sensitivity to glycolysis and IGFR inhibitors in melanoma with KMT2D-inactivating mutations. Graphical Abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|