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A new insight into how some cancers begin

Professor Salvador Aznar-Benitah and his team at the IRB Barcelona have identified two new proteins that, when faulty, can allow cancer to begin. They are now looking into ways to stop these faulty proteins and possibly help develop a new treatment for cancer in the longer-term. This work was recently published in eLife.

The scientists were investigating two proteins called Dnmt3a and Dnmt3b. The role of these proteins is to modify our DNA to ensure specific genes are switched on in some cells but not others. The reason this is so important is because our bodies are made of many different types of cell, such as nerve cells or skin cells, which perform very different jobs. Yet most of the cells in our body contain the same DNA – so how do the cells know which cell type they are supposed to be?

The answer lies in our genes – short sections of DNA which are code for making proteins. In each cell type, only certain sets of genes are switched on to become active. Proteins known as ‘epigenetic regulators’ are responsible for producing the different gene activity. If epigenetic regulators are switched on or off at the wrong time, they can contribute to ageing and diseases such as cancer.

How is DNA regulated?

One group of epigenetic regulators are proteins known as DNA methyltransferases. They control the activity of genes by adding small chemical groups known as methyl groups on to the DNA. Dnmt3a and Dnmt3b are both DNA methyltransferases and are crucial during development to help cells mature and specialize into different types. They are also mutated or less active in some skin cancers and various other cancers.

Professor Aznar Benitah investigated the role these proteins play in adult mice. The experiments showed that under ordinary laboratory conditions, mutant mice where Dnmt3a and Dnmt3b have been removed, were as healthy as normal mice.

Understanding how these proteins protect cells from cancer

When the mice were exposed to chemicals however, which mimic skin exposure to UV light and promote tumour growth, the mutant mice developed many more skin tumors than the normal mice. Furthermore, the tumors were more likely to form secondary tumors in the lung. These findings indicate a key role for Dnmt3a and Dnmt3b in protecting cells from cancer.

When the team tried to investigate how the proteins had this protective effect, they found that Dnmt3a reduced the production of a protein called PPAR-γ, which helps to break down some types of fat molecules. To combat the loss of Dnmt3a the researchers treated the mutant mice with a drug that stops PPAR-γ activity which they found slowed the growth of the tumors.

Overall, these experiments show a new way in which DNA methyltransferases act in animals.

Dr Lara Bennett from Worldwide Cancer Research commented “These are extremely interesting findings. Future research will investigate whether drugs that stop the breakdown of fats could help to treat cancers in which the Dnmt3a and Dnmt3b proteins are mutated or less active. If the future research is successful, it may lead to a new drug which could potentially help prevent or treat cancer.”

Recently, Professor Benitah’s team were at the centre of an important discovery about how cancer spreads which is having a huge impact on the cancer field. Read more here.

Rinaldi et al. Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ, eLIFE (2017). DOI: 10.7554/eLife.21697

Image courtesy of Helen Young shows skin cells with melanoma skin cancer cells shown in green.