Cell Reports (Oct 2020)
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. Axelrad,
- Nazanin 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
Affiliations
- Mayinuer Maitituoheti
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Emily Z. Keung
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Ming Tang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Liang Yan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Hunain Alam
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Guangchun Han
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Anand K. Singh
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Ayush T. Raman
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Quantitative Sciences, Baylor College of Medicine, Houston, TX, USA
- Christopher Terranova
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Sharmistha Sarkar
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Elias Orouji
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Samir B. Amin
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Sneha Sharma
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Maura Williams
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Neha S. Samant
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Mayura Dhamdhere
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Norman Zheng
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Tara Shah
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Amiksha Shah
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Jacob B. Axelrad
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Nazanin E. Anvar
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Yu-Hsi Lin
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Shan Jiang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Edward Q. Chang
- Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Davis R. Ingram
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Wei-Lien Wang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Alexander Lazar
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Min Gyu Lee
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Florian Muller
- Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Linghua Wang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Haoqiang Ying
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Kunal Rai
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Quantitative Sciences, Baylor College of Medicine, Houston, TX, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
- Journal volume & issue
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Vol. 33,
no. 3
p. 108293
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.
