@article{27027d46feb943c994094fe8bf0da8ef,
title = "KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer",
abstract = "Histone methyltransferase KMT2D is frequently mutated in lung tumors, and Alam et al. identify KMT2D as a lung tumor suppressor. KMT2D deficiency induces aberrant metabolic reprogramming via super-enhancer impairment, conferring sensitivity to glycolytic inhibitors in lung cancer with KMT2D-inactivating mutations.",
keywords = "epigenetic modifier, glycolysis, histone methylation, histone methyltransferase, inhibitor, KMT2D, lung cancer, metabolism, super-enhancer, tumor suppressor",
author = "Hunain Alam and Ming Tang and Mayinuer Maitituoheti and Dhar, {Shilpa S.} and Manish Kumar and Han, {Chae Young} and Ambati, {Chandrashekar R.} and Amin, {Samir B.} and Bingnan Gu and Chen, {Tsai Yu} and Lin, {Yu Hsi} and Jichao Chen and Muller, {Florian L.} and Nagireddy Putluri and Flores, {Elsa R.} and DeMayo, {Francesco J.} and Laura Baseler and Kunal Rai and Lee, {Min Gyu}",
note = "Funding Information: We are grateful to Julien Sage, Joseph R. Marszalek, and Laura Pasqualucci for providing their reagents and thank Haoqiang Ying for insightful discussion. We are also thankful to Kathryn Hale (Scientific Publications Services, Research Medical Library, The University of Texas MD Anderson Cancer Center) for the editorial assistance and to Zhenbo Han, Su Zhang, and Charles Kingsley for their technical assistance. This work was supported by grants to M.G.L. from the National Institutes of Health ( NIH ; R01CA157919 , R01CA207109 , and R01CA207098 ) and the Center for Cancer Epigenetics (Solexa allowance) at the MD Anderson Cancer Center , by a grant to K.R. from the NIH ( R00CA160578 ), by a grant to F.L.M. from American Cancer Society ( RSG-15-145-01-CDD ), by a grant to F.J.D. from the Intramural Research Program of the National Institute of Environmental Health Sciences ( Z1AES103311-10 ), by a grant to E.R.F. from the NIH ( R35CA197452 ), by grants to N.P. from the Cancer Prevention and Research Institute of Texas (The Proteomics and Metabolomics Core Facility, RP170005 ), the American Cancer Society ( 127430-RSG-15-105-01-CNE ), and the NIH ( R01CA216426 and R01CA220297 ), by a fellowship to M.K. from the Center for Cancer Epigenetics at the MD Anderson Cancer Center, and by a fellowship to H.A. from the Odyssey program at the MD Anderson Cancer Center. The animal imaging and histology work were performed at the Small Animal Imaging Facility and Histopathology Core Lab, respectively, at the MD Anderson Cancer Center, supported by the NIH National Cancer Institute ( P30CA016672 ). Funding Information: We are grateful to Julien Sage, Joseph R. Marszalek, and Laura Pasqualucci for providing their reagents and thank Haoqiang Ying for insightful discussion. We are also thankful to Kathryn Hale (Scientific Publications Services, Research Medical Library, The University of Texas MD Anderson Cancer Center) for the editorial assistance and to Zhenbo Han, Su Zhang, and Charles Kingsley for their technical assistance. This work was supported by grants to M.G.L. from the National Institutes of Health (NIH; R01CA157919, R01CA207109, and R01CA207098) and the Center for Cancer Epigenetics (Solexa allowance) at the MD Anderson Cancer Center, by a grant to K.R. from the NIH (R00CA160578), by a grant to F.L.M. from American Cancer Society (RSG-15-145-01-CDD), by a grant to F.J.D. from the Intramural Research Program of the National Institute of Environmental Health Sciences (Z1AES103311-10), by a grant to E.R.F. from the NIH (R35CA197452), by grants to N.P. from the Cancer Prevention and Research Institute of Texas (The Proteomics and Metabolomics Core Facility, RP170005), the American Cancer Society (127430-RSG-15-105-01-CNE), and the NIH (R01CA216426 and R01CA220297), by a fellowship to M.K. from the Center for Cancer Epigenetics at the MD Anderson Cancer Center, and by a fellowship to H.A. from the Odyssey program at the MD Anderson Cancer Center. The animal imaging and histology work were performed at the Small Animal Imaging Facility and Histopathology Core Lab, respectively, at the MD Anderson Cancer Center, supported by the NIH National Cancer Institute (P30CA016672). H.A. planned and carried out a majority of experiments, analyzed data, prepared figures, and wrote the manuscript. M.T. performed the bioinformatics analysis of RNA-seq and ChIP-seq data, prepared bioinformatics figures, and wrote the manuscript. M.M. performed ChIP-seq experiments. S.S.D. performed ChIP and rescue experiments. M.K. performed cell death and enzyme assays. C.Y.H. prepared reagents and performed Seahorse experiments and data analysis. S.B.A. contributed to data analysis. T-Y.C. contributed to inhibitor experiments. B.G. helped animal experiments. J.C. contributed to IHC experiments and analysis. C.R.A.and N.P. analyzed metabolite data. Y.-H.L. F.L.M. E.R.F. and F.J.D. provided reagents. L.B. analyzed tumor data. K.R. directed ChIP-seq experiments, guided the bioinformatics study, contributed to experiment design, and wrote the manuscript. M.G.L. conceived the study, designed and oversaw the study, evaluated data, and wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "13",
doi = "10.1016/j.ccell.2020.03.005",
language = "English (US)",
volume = "37",
pages = "599--617.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}