Methyl-DNA binding Proteins To Fight Cancer

Russians researchers are exploring the possibility for using Kaiso protein for early detection of cancer.

They are developing this new approach to treat intestinal cancer at the Bioengineering Centre, Russian Academy of Sciences, under Anna Prokhorchuk's guidance jointly with American colleagues sponsored by the international CRDF foundation and the Federal Agency for Science and Innovation.

Any cancerous disease changes the genetic landscape - some genes are suppressed and others get activated, resulting in the growth of the tumor and the formation of metastases, and cancer spreads beyond the control of the immune system.

The universal mechanism that regulates genetic activity is DNA methylation, where a methyl group is joined to a section of a molecule. Special methyl-DNA binding proteins spring into action, bond with a section of the methylated DNA and suppress gene activity. One such protein that the researchers are interested in is Kaiso. They assume that this protein plays an important role in the intestine cancer development, and knowledge about it can be used for diagnostics and treatment.

First, the researchers measured the level of expression of the Kaiso protein gene in intestinal tumors in mice and in human patients. The level of expression turned out to be dozens of times higher than that in healthy organs and tissues. ‘Kaiso-zero' mice were then used which were found to be resistant to cancer. The same resistance to cancer was acquired by the mice whose DNA methylation had been suppressed by other methods.

The Kaiso protein can be potentially used for early detection of cancer, as its content in a majority of tumors is much higher than that in human healthy tissue.

Contemporary molecular methods allow the analysis of expression of dozens of genes in the cancerous tissues, and comparison of the resultant picture with the gene portrait of normal cells. Of course, the Kaiso gene is not the only one that can be used for such diagnostics. The cancer tumor is a highly heterogeneous dynamic system, which requires knowledge of almost the entire genetic profile containing 28,000 genes.

Researchers believe that there are another 10 and 30 key genes that can also serve as tumor characteristic markers. This will save resources and time, sparing the need of analyzing the entire genomic profile.

In cancer therapy, chimeric Kaiso protein could be created. The ordinary Kaiso protein (via DNA methylated binding) inhibits the work of cancer suppressor genes. However, using the same properties of the protein, it is possible to make it reinforce the work of these genes. This is what the researchers are struggling to achieve.

"There are hidden pitfalls here," explains Anna Prokhorchuk, project manager. "It is necessary to make chimeric Kaiso work only to activate cancer suppressor genes, not the other methylated DNA sequences. This is what we are working at in the Bioengineering Centre jointly with American colleagues."