Researchers at the Fox Chase Cancer Centre, Philadelphia, USA, have elucidated the mechanism behind one form of gene silencing, which may open up a new route to cancer treatment.
During the development of healthy cells, genes that no longer need to be expressed are selectively 'switched off', or silenced, through methylation – the addition of a chemical group to specific DNA bases. However, aberrant gene silencing through this process can switch off essential genes and cause cells to become cancerous.
Some cancer drugs already work through demethylation, but this process is non-specific, which can cause side effects and other problems, Dr Alfonso Bellacosa, an associate professor at Fox Chase, explained. Using a specific process it could be possible to turn on incorrectly silenced genes, leading to potential cancer therapeutics that target the mechanisms underlying cancer development.
While it has been known for a number of years that cells use methylation to silence genes, it has not been clear how this is managed – how unmethylated regions are protected from unwanted methylation, and how unwanted methyl groups are removed. This research, published in Cell, has linked the process with an enzyme usually used in DNA repair, thymine DNA glycosylase (TDG).
The team, including scientists from France, Italy, and the USA, selectively inactivated TDG in mice; a change that proved lethal for a number of the resulting mouse embryos. Genetic analysis of those that did not survive showed disordered DNA methylation.
The researchers concluded that TDG was required for normal embryo development, because it established correct patterns of methylation in the specific regions of DNA that allow gene expression. TDG, along with others, including a damage response protein, protects DNA from methylation as well as specifically demethylating it.
'Since we now know there are proteins that actively affect demethylation, then we can imagine a new type of cancer therapy that demethylates specific genes. We would have a more precise and more targeted type of therapy', said Dr Bellacosa.
The technique could also have potential in other disorders caused by changes in DNA methylation, but it is still in its early stages and the next step will be to work out how to target specific genes for demethylation.
'This is a very fundamental study that gets at the process by which genes are turned on or turned off', Dr Bellacosa added. 'We may be several years away from taking full advantage of this new knowledge. But we will get there'.