Study finds that protein that usually prevents mutation can be transformed into protector of cancer cells.
Under normal conditions, the CHD4 protein is helpful: it stops cells from transcribing faulty DNA, thereby eliminating potential mutation. However, in colon cancer and perhaps other kinds of cancer as well, it appears that this protein becomes a kind of double agent, working for the enemy.

This is the finding in a new study by researchers at the University of Maryland School of Medicine (UM SOM) and Johns Hopkins University. This is the first time the protein has been shown to play a role in initiating and maintaining cancer; it opens up a new way to understand how cancer evades the body’s defenses. The discovery may one day lead to new treatments that could prevent the protein from becoming a double agent, or use it as a biomarker for cancer appearance or recurrence.

The findings were published in the journal Cancer Cell.

“No one knew this protein was involved in initiating and maintaining cancer,” said one of the study’s lead authors, Feyruz V. Rassool, PhD, Associate Professor in the Department of Radiation Oncology at UM SOM. “Now that we have identified it as a potential bad actor, we can begin to focus on how we can stop it, or use it as a way to predict the course of the disease.” The other lead researchers on the article are Limin Xia, a postdoctoral fellow and Stephen B. Baylin, MD, the Virginia and D.K. Ludwig Professor of Oncology and Medicine and associate director for research programs at the Kimmel Cancer Center.

The experiments took place in human colon cancer cells and mice. The results provide further evidence that cancer arises when a normal part of cell machinery generally used to repair DNA damage is diverted from its usual task. If confirmed, the findings could lead to the identification of new molecular targets for anticancer drugs or tests for cancer recurrence.

Scientists have known that cancer cells’ ability to spread is in part due to so–called “epigenetic” factors that sabotage the ability of genes to turn on or off when they should. Now, the scientists uncovered a link between this a particular protein, CHD4, and this cancer–related genetic switch–off. CHD4, which is short for chromodomain helicase DNA–binding protein, appears to play a role in DNA damage repair.

The researchers exposed human colon cancer cells in the laboratory to hydrogen peroxide, which damages DNA. The experiments showed that CHD4 was present at the DNA damage sites within minutes of exposure to hydrogen peroxide, and was soon accompanied by other reparative proteins, including some that turn genes on and off.

The researchers also used a laser beam to cause DNA damage in the colon cancer cell lines. Again, CHD4 and its crew of repair and “epigenetic” proteins swooped into the damage site.

Presumably, Baylin says, the mechanism exists to shut down genes in damaged regions while cells repair DNA. However, he says, the repair team may stick around in some genes, keeping them turned off even after DNA repair is finished or ongoing.

The type of gene that is kept turned off could be linked to cancer, notes the team. The researchers found that eight genes most likely to be turned off in colon cancer cells are thought to be potential tumor suppressors. Further investigation showed that these genes were also already enriched with CHD4. When researchers prevented cells from making CHD4, these genes reactivated, and were able to produce proteins that prevented the spread of cancer cells.

The investigators also reviewed other studies, and found that many colon, lung and other cancers – between 30 and 40 percent – had much higher levels of CHD4 than healthy tissues.