@article{f0183fe3049d40b98f5bae334f0546bf,
title = "Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma",
abstract = "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.",
keywords = "2-DG, IGFBP5, KMT2D, Linsitinib, RNAi screen, chromatin, epigenetics, glycolysis, melanoma, mouse model",
author = "Mayinuer Maitituoheti and Keung, {Emily Z.} and Ming Tang and Liang Yan and Hunain Alam and Guangchun Han and Singh, {Anand K.} and Raman, {Ayush T.} and Christopher Terranova and Sharmistha Sarkar and Elias Orouji and Amin, {Samir B.} and Sneha Sharma and Maura Williams and Samant, {Neha S.} and Mayura Dhamdhere and Norman Zheng and Tara Shah and Amiksha Shah and Axelrad, {Jacob B.} and Anvar, {Nazanin E.} and Lin, {Yu Hsi} and Shan Jiang and Chang, {Edward Q.} and Ingram, {Davis R.} and Wang, {Wei Lien} and Alexander Lazar and Lee, {Min Gyu} and Florian Muller and Linghua Wang and Haoqiang Ying and Kunal Rai",
note = "Funding Information: We thank Marcus Coyle, Curtis Gumbs, and SMF core at MDACC for sequencing support. We thank Yanping Cao, Jill Garvey, Ibarra Ivonne, and Kun Zhao for mouse colony maintenance. The work described in this article was supported by grants from the National Institutes of Health (CA160578 and CA222214 to K.R.; CA157919, CA207109, and CA207098 to M.G.L.; and CA016672 to SMF Core), American Cancer Society (RSG-15-145-01-CDD to F.M.), Center for Cancer Epigenetics at MDACC (K.R.), and MD Anderson Cancer Center (start-up funds to K.R.). The following fellowship support is acknowledged: K.R. (Charles A. King postdoctoral fellowship) and H.A. (Odyssey Fellowship at MD Anderson Cancer Center). The histology work were performed at the Histopathology Core Lab at the UT MD Anderson Cancer Center supported by the NIH National Cancer Institute (P30CA016672). M.M. planned and carried out experiments, analyzed data, prepared figures, and wrote the manuscript. E.Z.K. performed experiments, analyzed data, and wrote the manuscript. M.T. performed the bioinformatics analysis of TCGA and CCLE/GDC data. H.A. provided reagents and helped with preparation of figures. L.Y. and H.Y. performed metabolic experiments and helped with data analysis. G.H. and. L.W. contributed to the TCGA data analysis. A.K.S. provided help with experimentation. A.T.R. C.T. and. S.B.A. helped with informatics analysis. S. Sarkar contributed to study design and provided help with experimentation. E.O. S. Sharma, M.W. N.S.S. M.D. N.Z. T.S. A.S. J.B.A. and N.E.A. provided technical help. S.J. provided support for mouse colony maintenance and experimental help. E.Q.C. contributed to IHC experiments and analysis. A.L. provided guidance on mouse tumor pathology. Y.-H.L. and F.M. provided reagents. K.R. conceived and designed the study, performed experiments, evaluated data, made figures, and wrote the manuscript. The authors declare no competing interests. Funding Information: We thank Marcus Coyle, Curtis Gumbs, and SMF core at MDACC for sequencing support. We thank Yanping Cao, Jill Garvey, Ibarra Ivonne, and Kun Zhao for mouse colony maintenance. The work described in this article was supported by grants from the National Institutes of Health ( CA160578 and CA222214 to K.R.; CA157919 , CA207109 , and CA207098 to M.G.L.; and CA016672 to SMF Core), American Cancer Society ( RSG-15-145-01-CDD to F.M.), Center for Cancer Epigenetics at MDACC (K.R.), and MD Anderson Cancer Center (start-up funds to K.R.). The following fellowship support is acknowledged: K.R. ( Charles A. King postdoctoral fellowship ) and H.A. ( Odyssey Fellowship at MD Anderson Cancer Center ). The histology work were performed at the Histopathology Core Lab at the UT MD Anderson Cancer Center supported by the NIH National Cancer Institute ( P30CA016672 ). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = oct,
day = "20",
doi = "10.1016/j.celrep.2020.108293",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}