The loss of protein Dnmt3a increases the number of carcinogen-induced squamous tumours

Representative images of different subtypes of skin tumors (L. Rinaldi, IRB Barcelona)

Researchers led by Salvador Aznar-Benitah at IRB Barcelona investigate the role of Dnmt3a and Dnmt3b proteins in skin homeostasis and tumour development in adult mice.

The study has been published in eLife and deserved an eLife digest aimed at a more general audience.

ELife digest feature: DOI: http://dx.doi.org/10.7554/eLife.21697.002

Most of the cells in our body contain the same DNA. However, our bodies are made of many different types of cell, such as nerve cells or skin cells, which perform very different jobs. In each cell type only certain sets of genes encoded by the DNA are active. Proteins known as epigenetic regulators are responsible for producing the different patterns of gene activity. If epigenetic regulators are switched on or off at the wrong time, they can contribute to ageing and diseases such as cancer.

Enzymes known as DNA methyltransferases are one group of epigenetic regulators. DNA methyltransferases control the activity of genes by adding small chemical groups known as methyl groups to the DNA. Two of these enzymes – known as Dnmt3a and Dnmt3b – are important during development to help cells mature and specialize into different types. Mice that lack both of these enzymes either die as embryos or just after birth. Furthermore, these enzymes are mutated or less active in some skin cancers and various other human cancers.

In a study published in eLife, led by Salvador Aznar Benitah, ICREA research professor and group leader of the Stem Cells and Cancer laboratory, Rinaldi et al. investigated the role these enzymes play in adult mice. The experiments show that under ordinary laboratory conditions, mutant mice that lacked Dnmt3a and Dnmt3b were as healthy as normal mice. However, when the mice were exposed to chemicals that promote tumour growth, which mimics skin exposure to UV light, the mutant mice developed many more skin tumours than the normal mice. Furthermore, the tumours in the mutant mice were more likely to form secondary tumours in the lung. Rinaldi et al. found that Dnmt3a reduced the production of a protein called PPAR-γ, which helps to break down some types of fat molecules. Treating the mutant mice with a drug that inhibits PPAR-γ activity slowed the growth of the tumours.

Overall, these experiments show a new way in which DNA methyltransferases act in adult animals. Future research will investigate whether drugs that inhibit the breakdown of fats could help to treat cancers in which the Dnmt3a and Dnmt3b proteins are mutated or less active.

Reference article:
Lorenzo Rinaldi, Alexandra Avgustinova, Mercè Martín, Debayan Datta, Guiomar Solanas, Neus Prats, Salvador Aznar Benitah
Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ
eLife (2017). DOI: http://dx.doi.org/10.7554/eLife.21697