EHMT2 methyltransferase governs cell identity in the lung and is required for KRASG12D tumor development and propagation
- Surrozen, United States
- Oric Pharma, United States
- Genentech, Inc, United States
- Stanford University, United States
- Scorpion Therapeutics, United States
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 KrasG12D tumors and normal AT2 cells - the predominant cell of origin of this cancer. Consequently, EHMT2 inhibition prevents KrasG12D 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
Article and author information
Author details
Melissa R Junttila
Funding
The authors declare that there was no funding for this work.
Reviewing Editor
- Martin McMahon, University of Utah Medical School, United States
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).
Version history
- Received: April 7, 2020
- Preprint posted: April 20, 2020 (view preprint)
- Accepted: August 16, 2022
- Accepted Manuscript published: August 19, 2022 (version 1)
- Version of Record published: September 2, 2022 (version 2)
Copyright
© 2022, pribluda et al.
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.
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EHMT2 methyltransferase governs cell identity in the lung and is required for KRASG12D tumor development and propagation
eLife 11:e57648.
https://doi.org/10.7554/eLife.57648
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