Cited by 255Chromatin Remodeling and CancerCancer, Hypoxia, and MetabolismEpigenetics and DNA Methylation

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KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

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Alam, Hunain, Tang, Ming, Maitituoheti, Mayinuer, Dhar, Shilpa S., Kumar, Manish, Han, Chae Young, Ambati, Chandrashekar R., Amin, Samir B., Gu, Bingnan, Chen, Tsai-Yu, Lin, Yu-Hsi, Chen, Jichao, Muller, Florian L., Putluri, Nagireddy, Flores, Elsa R., DeMayo, Francesco J., Baseler, Laura, Rai, Kunal, Lee, Min Gyu·2020·Cancer Cell

DOI 10.1016/j.ccell.2020.03.005PMC PMC7178078

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Abstract

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.

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Authors: Alam, H., Tang, M., Maitituoheti, M., Dhar, S. S., Kumar, M., Han, C. Y., Ambati, C. R., Amin, S. B., Gu, B., Chen, T.-Y., Lin, Y.-H., Chen, J., Muller, F. L., Putluri, N., Flores, E. R., DeMayo, F. J., Baseler, L., Rai, K., & Lee, M. G.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Baylor College of Medicine (US)
Moffitt Cancer Center (US)
National Institute of Environmental Health Sciences (US)
Corresponding author: Rai, Kunal
Lee, Min Gyu
ORCID: Alam, Hunain
Tang, Ming
Maitituoheti, Mayinuer
Dhar, Shilpa S.
Kumar, Manish
Han, Chae Young
Ambati, Chandrashekar R.
Chen, Tsai-Yu
Lin, Yu-Hsi
Chen, Jichao
Putluri, Nagireddy
Flores, Elsa R.
DeMayo, Francesco J.
Rai, Kunal
Lee, Min Gyu
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2020-04
Volume: 37
Issue: 4
Pages: 599-617.e7
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2020.03.005
PMC: PMC7178078
OpenAlex: W3014830213
Cited by: 243
References: 102
Citations by year: 2026: 28 · 2025: 39 · 2024: 38 · 2023: 53 · 2022: 42 · 2021: 35 · 2020: 8
FWCI: 11.99
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 377 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: University of Texas MD Anderson Cancer Center (R00CA160578)
National Cancer Institute (P30CA016672)
American Cancer Society (RSG-15-145-01-CDD)
National Institutes of Health (R01CA207109, R01CA157919, R01CA207098)
National Institute of Environmental Health Sciences (Z1AES103311-10, R35CA197452)
Cancer Prevention and Research Institute of Texas (RP170005, 127430-RSG-15-105-01-CNE)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords: KMT2D, histone methyltransferase, lung cancer, super-enhancers, enhancers, glycolysis, glycolysis inhibitors, Per2, circadian rhythm, tumor suppressor, epigenetic regulators, loss-of-function mutations, lung carcinogenesis
MeSH terms: Adenocarcinoma of Lung, Animals, Antimetabolites, Deoxyglucose, DNA-Binding Proteins, Enhancer Elements, Genetic, Glycolysis, Histones, Humans, Lung Neoplasms, Mice, Nude, Mutation, Neoplasm Proteins, Prognosis, Histone-Lysine N-Methyltransferase, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Apoptosis, Mice, Knockout, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Myeloid-Lymphoid Leukemia Protein, Period Circadian Proteins

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KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

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