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

Lorenzo Rinaldi1,2,3, Alexandra Avgustinova1, Mercè Martín1

  • 1Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.

Elife
|April 21, 2017
PubMed

Insights

DNA methyltransferases Dnmt3a and Dnmt3b protect the skin from cancer. Loss of Dnmt3a increases squamous tumors, while combined loss of both promotes aggressive, metastatic carcinomas.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Dermatology

Background:

  • DNA methyltransferases (DNMTs) regulate gene expression through DNA methylation.
  • Dnmt3a and Dnmt3b roles in tumorigenesis are not fully understood, particularly in epithelial cancers.
  • Previous studies suggest Dnmt3a suppresses, while Dnmt3b promotes, tumorigenesis.

Purpose of the Study:

  • To investigate the roles of Dnmt3a and Dnmt3b in epidermal homeostasis and skin tumorigenesis.
  • To elucidate the mechanisms by which Dnmt3a and Dnmt3b influence squamous tumor development and progression.
  • To determine the therapeutic potential of targeting pathways regulated by Dnmt3a in skin cancer.

Main Methods:

  • Utilized genetically engineered mouse models with conditional deletion of Dnmt3a and Dnmt3b in the epidermis.
  • Induced squamous tumors using chemical carcinogens.
  • Analyzed tumor incidence, progression, and metastasis.
  • Performed molecular analyses including gene expression profiling, chromatin immunoprecipitation, and promoter methylation analysis.
  • Investigated the role of PPAR-γ inhibition in modulating Dnmt3a-deficient tumorigenesis.

Main Results:

  • Dnmt3a and Dnmt3b are dispensable for normal murine epidermis homeostasis.
  • Loss of Dnmt3a, but not Dnmt3b, significantly increases the number of carcinogen-induced squamous tumors.
  • Combined deletion of Dnmt3a and Dnmt3b leads to more aggressive and metastatic squamous carcinomas.
  • Dnmt3a promotes epidermal differentiation gene expression and inhibits lipid metabolism genes, including PPAR-γ, via promoter methylation.
  • Inhibition of PPAR-γ partially rescues the increased tumorigenesis observed upon Dnmt3a deletion.

Conclusions:

  • Dnmt3a and Dnmt3b function as tumor suppressors in the epidermis.
  • Dnmt3a plays a critical role in preventing squamous tumor formation and progression.
  • Combined loss of Dnmt3a and Dnmt3b promotes aggressive squamous carcinoma development and metastasis.
  • Targeting PPAR-γ represents a potential therapeutic strategy for squamous carcinomas with Dnmt3a deficiency.
Keywords:
DNA methylationPPARgcancer biologydevelopmental biologyenhancersmousepromoterssquamous cell carcinomasstem cellstranscriptional regulation

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