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How Cancer Turns a Good Protein Into A Double Agent

May 10, 2017 | David Kohn

Feyruz V. Rassool, PhD

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 this week 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.

damage sites

CHD4 at DNA domain sites in a colon cancer cell at one, five and 15 minutes.

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.

“This result suggests that the presence of CHD4 and its accompanying proteins may be part of a universal system for repairing DNA damage,” says Dr. Baylin. Adding support to that idea, he says, when the team stopped cells from making CHD4 by genetically disrupting the gene, the accompanying proteins were no-shows after exposure to hydrogen peroxide or the laser.

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.

The researchers were also curious about how CHD4 is drawn to damaged DNA. They found that CHD4 interacts directly with an enzyme called 8-oxoguanine glycosylase (OGG1), which removes guanine — one of the units that makes up DNA — when it becomes damaged. When the researchers removed this enzyme from cells, CHD4 failed to arrive at sections of damaged DNA.

When the researchers color-stained the DNA of colon cancer cells to find the most likely locations of OGG1, they found it at the locations of the eight tumor suppressor genes that are often turned off when cancer occurs. This suggests that CHD4 may play a key role in suppressing these tumor suppressor genes.

Finally, the researchers performed a series of experiments to compare the behavior of two sets of colon cancer cells: one set with a characteristically high amount of CHD4, and one in which the researchers had used genetic techniques to reduce levels of the protein.

The researchers found that the unmodified colon cancer cells were very active: they readily moved around a petri dishes, penetrated other cell membranes there, and migrated from one area to another in live mice to create new tumors. By comparison, the low-CHD4 cells had none of these capabilities.

Together, these experiments suggest that CHD4 plays a key role in causing colon cancer, and perhaps other kinds of cancer too.

Finding ways to reduce the amount of CHD4 in tumors could be one way to treat cancer. And tracking levels of OGG1, the enzyme that attracts CHD4, might be useful to gauge the risk of cancer recurrence.

Dr. Rassool is an expert in repair of potentially lethal forms of DNA damage, which play a critical role in generating genomic instability. Her work has focused on the aberrant expression and activity of these repair pathways in cancer and leukemia cells, which not only play a role in genomic instability, but also appear critical for these cells’ survival. She is now studying the use of DNA repair components as a novel therapeutic strategy for patients with leukemias and other cancers.

“Cancer continues to be one of our greatest public health problems,” said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. “This collaborative project has illuminated a key aspect of the genetics of tumor suppression in colon cancer, and perhaps other cancers as well. It points to new areas of research in both treatment and biomarkers.”

About the University of Maryland School of Medicine

Celebrating its 210th Anniversary, the University of Maryland School of Medicine was chartered in 1807 and is the first public medical school in the United States and continues today as an innovative leader in accelerating innovation and discovery in medicine. The School of Medicine is the founding school of the University of Maryland and is an integral part of the 11-campus University System of Maryland. Located on the University of Maryland’s Baltimore campus, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide a research-intensive, academic and clinically based education. With 43 academic departments, centers and institutes and a faculty of more than 3,000 physicians and research scientists plus more than $400 million in extramural funding, the School is regarded as one of the leading biomedical research institutions in the U.S. with top-tier faculty and programs in cancer, brain science, surgery and transplantation, trauma and emergency medicine, vaccine development and human genomics, among other centers of excellence. The School is not only concerned with the health of the citizens of Maryland and the nation, but also has a global presence, with research and treatment facilities in more than 35 countries around the world.


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