Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ

Abstract

The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism genes, including PPAR-γ, by directly methylating their promoters. Importantly, inhibition of PPAR-γ partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis, and that squamous carcinomas are sensitive to inhibition of PPAR-γ.

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Article and author information

Author details

  1. Lorenzo Rinaldi

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Alexandra Avgustinova

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Mercé Martin

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Debayan Datta

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Guiomar Solanas

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Neus Prats

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Salvador Aznar Benitah

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    salvador.aznar-benitah@irbbarcelona.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9059-5049

Funding

National Grant, Spanish Ministry of Economy and Development (BFU2013-47990-P)

  • Lorenzo Rinaldi
  • Alexandra Avgustinova
  • Debayan Datta
  • Guiomar Solanas
  • Salvador Aznar Benitah

European Research Council (STEMCLOCK (309502))

  • Lorenzo Rinaldi
  • Alexandra Avgustinova
  • Guiomar Solanas
  • Salvador Aznar Benitah

Foundation Botin (No reference associated)

  • Lorenzo Rinaldi
  • Alexandra Avgustinova
  • Debayan Datta
  • Guiomar Solanas
  • Salvador Aznar Benitah

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the European Union. All of the animals were handled according to approved institutional animal care and use committee (CEEA) protocols (SAB-13-1522) of the Scientific Parc of Barcelona (PCB). The protocol was approved by the Committee on the Ethics of Animal Experiments of the Government of Catalunya.

Version history

  1. Received: September 21, 2016
  2. Accepted: April 13, 2017
  3. Accepted Manuscript published: April 20, 2017 (version 1)
  4. Version of Record published: May 12, 2017 (version 2)

Copyright

© 2017, Rinaldi 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. Lorenzo Rinaldi
  2. Alexandra Avgustinova
  3. Mercé Martin
  4. Debayan Datta
  5. Guiomar Solanas
  6. Neus Prats
  7. Salvador Aznar Benitah
(2017)
Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ
eLife 6:e21697.
https://doi.org/10.7554/eLife.21697

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https://doi.org/10.7554/eLife.21697

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