Scientists make key cancer discovery

A hallmark of cancer is unrestricted cell growth, which begins when gene mutations "turn off" or "silence" genes that regulate cell growth. Now researchers at Huntsman Cancer Institute have identified two enzymes that can combine to "turn on" silenced genes and may also prevent gene silencing. That could put treatment or even a cure in reach if scientists can learn how to use this pair of enzymes to turn on key genes at will.

In findings published in the Dec. 26 issue of the journal Cell, the researchers found using zebrafish that the pair of enzymes seem to control the 'on-off' switch for genes that may trigger cancer, said Brad Cairns, a Howard Hughes Medical Institute investigator, and professor of oncological sciences at the University of Utah and HCI.

Zebrafish are genetically very much like humans in how they control cancer initiation. Using zebrafish, researchers discovered how a combination of a 5-meC deaminase enzyme, a G:T glycosylase enzyme and the gene Gadd45 regulates the levels of DNA methylation on genes. Methylation, the adding of methyl, silences genes, while demethylation turns on genes. In a well-functioning system, genes are turned on or off as appropriate during various points in development or imprinting.

DNA is made of four bases. Of those four, only cytosine can receive a methyl modification, which recruits potent gene silencing machinery that will turn off the underlying genes, Cairns said. It's the equivalent of a gene knockout mutation and it's normally used to combat viruses that infect DNA. However, during cancer, this methylation system is improperly directed to healthy genes, and turns off or silences tumor-suppression genes, leading to cancer.

The key finding is the discovery of the use of two enzymes and a regulator to remove DNA methylation, which may allow genes to be turned back on. For a long time, Cairns said, scientists believed they would find a single special enzyme that simply removes the methyl from cytosine, but failed. The surprise was finding that the methyl was not removed, rather a pair of enzymes combined to remove the entire methyl-cytosine, leading to its replacement of a fresh unmethylated cytosine, which does not attract silencing machinery.

"We may have the ability now by learning more about these enzymes to target demethylation to those tumor suppressors so they get turned back on again," Cairns said.

Problems with DNA methylation are "strongly associated" with early development of cancer, some diseases and birth defects, so the discovery of the two enzymes involved is significant and HCI has applied for a patent. Cairns said the researchers believe the process can be reversed. They hope drugs might be developed to reactivate particular genes and suppress tumor growth.