1. Cancer Biology
  2. Cell Biology

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

  1. Ariel pribluda
  2. Anneleen Daemen
  3. Anthony Nelson Lima Mr.
  4. Xi Wang
  5. Marc Hafner
  6. Chungkee Poon
  7. Zora Modrusan
  8. Anand Kumar Katakam
  9. Oded Foreman
  10. Jefferey Eastham
  11. Jefferey Hung
  12. Benjamin Haley
  13. Julia T Garcia
  14. Erica L Jackson
  15. Melissa R Junttila  Is a corresponding author
  1. Surrozen, United States
  2. Oric Pharma, United States
  3. Genentech, Inc, United States
  4. Stanford University, United States
  5. Scorpion Therapeutics, United States
https://doi.org/10.7554/eLife.57648
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Cite this article
  1. Ariel pribluda
  2. Anneleen Daemen
  3. Anthony Nelson Lima Mr.
  4. Xi Wang
  5. Marc Hafner
  6. Chungkee Poon
  7. Zora Modrusan
  8. Anand Kumar Katakam
  9. Oded Foreman
  10. Jefferey Eastham
  11. Jefferey Hung
  12. Benjamin Haley
  13. Julia T Garcia
  14. Erica L Jackson
  15. Melissa R Junttila
(2022)
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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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

The following previously published data sets were used

Article and author information

Author details

  1. 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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2817-2827

  2. 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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6287-7105

  3. 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.

  4. Xi Wang

    Department of Translational Oncology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Xi Wang, holds shares in the company.

  5. Marc Hafner

    Department of Bioinformatics and Computational Biology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Marc Hafner, holds shares in the company.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1337-7598

  6. Chungkee Poon

    Department of Immunology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Chungkee Poon, holds shares in the company.

  7. Zora Modrusan

    Department of Molecular Biology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Zora Modrusan, holds shares in the company.

  8. Anand Kumar Katakam

    Department of Pathology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Anand Kumar Katakam, holds shares in the company.

  9. Oded Foreman

    Department of Pathology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Oded Foreman, holds shares in the company.

  10. Jefferey Eastham

    Department of Pathology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Jefferey Eastham, holds shares in the company.

  11. Jefferey Hung

    Department of Pathology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Jefferey Hung, holds shares in the company.

  12. Benjamin Haley

    Department of Molecular Biology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Benjamin Haley, holds shares in the company.

  13. 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..

  14. 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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7100-8021

  15. 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..
    ORCID icon "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

© 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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  1. Ariel pribluda
  2. Anneleen Daemen
  3. Anthony Nelson Lima Mr.
  4. Xi Wang
  5. Marc Hafner
  6. Chungkee Poon
  7. Zora Modrusan
  8. Anand Kumar Katakam
  9. Oded Foreman
  10. Jefferey Eastham
  11. Jefferey Hung
  12. Benjamin Haley
  13. Julia T Garcia
  14. Erica L Jackson
  15. Melissa R Junttila
(2022)
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

Share this article

https://doi.org/10.7554/eLife.57648

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