Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma
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 g...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720312821 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mayinuer Maitituoheti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T07:46:19Z |
| format | Article |
| id | doaj.art-c36af48cd2dc464096d008d1f2795abf |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T07:46:19Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c36af48cd2dc464096d008d1f2795abf2022-12-22T01:57:11ZengElsevierCell Reports2211-12472020-10-01333108293Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant MelanomaMayinuer Maitituoheti0Emily Z. Keung1Ming Tang2Liang Yan3Hunain Alam4Guangchun Han5Anand K. Singh6Ayush T. Raman7Christopher Terranova8Sharmistha Sarkar9Elias Orouji10Samir B. Amin11Sneha Sharma12Maura Williams13Neha S. Samant14Mayura Dhamdhere15Norman Zheng16Tara Shah17Amiksha Shah18Jacob B. Axelrad19Nazanin E. Anvar20Yu-Hsi Lin21Shan Jiang22Edward Q. Chang23Davis R. Ingram24Wei-Lien Wang25Alexander Lazar26Min Gyu Lee27Florian Muller28Linghua Wang29Haoqiang Ying30Kunal Rai31Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Program in Quantitative Sciences, Baylor College of Medicine, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USAThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USAInstitute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720312821KMT2DchromatinepigeneticsmelanomaRNAi screenIGFBP5 |
| spellingShingle | 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 Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma Cell Reports KMT2D chromatin epigenetics melanoma RNAi screen IGFBP5 |
| title | Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma |
| title_full | Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma |
| title_fullStr | Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma |
| title_full_unstemmed | Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma |
| title_short | Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma |
| title_sort | enhancer reprogramming confers dependence on glycolysis and igf signaling in kmt2d mutant melanoma |
| topic | KMT2D chromatin epigenetics melanoma RNAi screen IGFBP5 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720312821 |
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