EHMT2 methyltransferase governs cell identity in the lung and is required for KRASG12D tumor development and propagation

Abstract
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Abstract

Lung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that EHMT2 methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate in mouse lung. Inhibition of EHMT2 induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, EHMT2 activity functions to support regenerative properties of Kras^G12D tumors and normal AT2 cells - the predominant cell of origin of this cancer. Consequently, EHMT2 inhibition prevents Kras^G12D lung adenocarcinoma tumor formation and propagation and disrupts normal AT2 cell differentiation. Consistent with these findings, low gene EHMT2 expression in human lung adenocarcinoma correlates with enhanced AT2 gene expression and improved prognosis. These data reveal EHMT2 as a critical regulator of Wnt signaling, implicating Ehmt2 as a potential target in lung cancer and other AT2-mediated lung pathologies.

Data availability

Code and data availability All source code used in this study has been made available in the R computer language, in a fully documented software and data package. This package is freely available under the Creative Commons 3.0 license and can be downloaded from https://github.com/anneleendaemen/G9a.CellIdentity.Lung

The following previously published data sets were used

1. Treutlein
(2014) High throughput quantitative whole transcriptome analysis of distal mouse lung epithelial cells from various developmental stages (E14.5, E16.5, E18.5 and adult)
NCBI Gene Expression Omnibus, GSE52583.

https://www.ncbi.nlm.nih.gov/gds/?Db=gds&DbFrom=pmc&Cmd=Link&LinkName=pmc_gds&IdsFromResult=4145853
1. The cancer genome atlas
(2014) Article Open Access Published: 09 July 2014 Comprehensive molecular profiling of lung adenocarcinoma
(https://cghub.ucsc.edu/.

https://tcga-data.nci.nih.gov/docs/publications/luad_2014/

Article and author information

Author details

Ariel pribluda

Discovery Biology, Surrozen, South San Francisco, United States

Competing interests
Ariel pribluda, was an employee of Genentech when the work was performed and may hold stock..

"This ORCID iD identifies the author of this article:" 0000-0003-2817-2827
Anneleen Daemen

Computational biology, Oric Pharma, South San Francisco, United States

Competing interests
Anneleen Daemen, was an employee of Genentech when the work was performed and may hold stock..

"This ORCID iD identifies the author of this article:" 0000-0001-6287-7105
Anthony Nelson Lima Mr.

Department of Translational Oncology, Genentech, Inc, South San Francisco, United States

Competing interests
Anthony Nelson Lima, holds shares in the company.
Xi Wang

Department of Translational Oncology, Genentech, Inc, South San Francisco, United States

Competing interests
Xi Wang, holds shares in the company.
Marc Hafner

Department of Bioinformatics and Computational Biology, Genentech, Inc, South San Francisco, United States

Competing interests
Marc Hafner, holds shares in the company.

"This ORCID iD identifies the author of this article:" 0000-0003-1337-7598
Chungkee Poon

Department of Immunology, Genentech, Inc, South San Francisco, United States

Competing interests
Chungkee Poon, holds shares in the company.
Zora Modrusan

Department of Molecular Biology, Genentech, Inc, South San Francisco, United States

Competing interests
Zora Modrusan, holds shares in the company.
Anand Kumar Katakam

Department of Pathology, Genentech, Inc, South San Francisco, United States

Competing interests
Anand Kumar Katakam, holds shares in the company.
Oded Foreman

Department of Pathology, Genentech, Inc, South San Francisco, United States

Competing interests
Oded Foreman, holds shares in the company.
Jefferey Eastham

Department of Pathology, Genentech, Inc, South San Francisco, United States

Competing interests
Jefferey Eastham, holds shares in the company.
Jefferey Hung

Department of Pathology, Genentech, Inc, South San Francisco, United States

Competing interests
Jefferey Hung, holds shares in the company.
Benjamin Haley

Department of Molecular Biology, Genentech, Inc, South San Francisco, United States

Competing interests
Benjamin Haley, holds shares in the company.
Julia T Garcia

Department of Genetics, Stanford University, Stanford, United States

Competing interests
Julia T Garcia, was an employee of Genentech when the work was performed and may hold stock..
Erica L Jackson

Scorpion Therapeutics, South San Francisco, United States

Competing interests
Erica L Jackson, was an employee of Genentech when the work was performed and may hold stock..

"This ORCID iD identifies the author of this article:" 0000-0002-7100-8021
Melissa R Junttila

Biology, Oric Pharma, South San Francisco, United States

For correspondence
melissa.junttila@oricpharma.com

Competing interests
Melissa R Junttila, was an employee of Genentech when the work was performed and may hold stock..

"This ORCID iD identifies the author of this article:" 0000-0003-3538-1192

Funding

The authors declare that there was no funding for this work.

Ethics

Animal experimentation: All animal studies were approved by the Institutional Animal Care and Use Committee at Genentech and adhere to the Guidelines for the Care and Use of Laboratory Animals (protocols 17-1217, 17-0107 and 18-1833 series).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.