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

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 ar...

Full description

Saved in:
Bibliographic Details
Published in:eLife 2017-04, Vol.6
Main Authors: Rinaldi, Lorenzo, Avgustinova, Alexandra, Martín, Mercè, Datta, Debayan, Solanas, Guiomar, Prats, Neus, Benitah, Salvador Aznar
Format: Article
Language:English
Subjects:
Adults
Animal models
Animals
Cancer Biology
Carcinogens
Carcinoma
Carcinoma, Squamous Cell - physiopathology
Cell division
Deoxyribonucleic acid
Developmental Biology and Stem Cells
DNA
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA methylation
DNA methyltransferase
DNA Methyltransferase 3A
DNA Methyltransferase 3B
Enhancers
Epidermis
Epidermis - physiology
Gene expression
Genetic transformation
Genomes
Hair
Homeostasis
Immunoglobulins
Keratin
Lipid metabolism
Lung cancer
Metastases
Mice
Peroxisome proliferator-activated receptors
PPAR gamma - metabolism
PPARg
promoters
Skin
Squamous cell carcinoma
squamous cell carcinomas
Stem cells
transcriptional regulation
Tumorigenesis
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.21697