Johns Hopkins Study Could Lead To Novel Molecular Targets For Anticancer Drugs


A new study conducted by a team of researchers at Johns Hopkins Kimmel Cancer Center reveals that cancer emerges when a common part of a cell’s machinery typically utilized to repair DNA damage is deflected from its normal task. The researchers note that the findings could very well lead to the ascertainment of new molecular targets for anticancer tests and drugs for cancer recurrence.

Researchers have known for a long time that chronic inflammation, a cancer risk factor, can cause damage to DNA and cancer cells have the ability to spread, because of “epigenetic” factors that destroy genes ability to switch on and off as they normally would. The researchers discovered a connection between those two incidents by focusing on a protein called CHD4 or chromodomain helicase DNA-binding protein, which correlates with DNA damage repair.

The series of studies were designed to determine how CHD4 proteins repair DNA damage.Human colon cancer cells were exposed to hydrogen peroxide, which is known to damage DNA via an inflammatory-like process, with the majority of focus being placed on highly reactive, negatively charged molecules known as reactive oxygen species (ROS). The studies revealed that CHD4 was present at the site of the DNA damage in minutes of exposure to the hydrogen peroxide and were joined by a “repair crew” of additional proteins, comprised partially of DNA methyltransferases, a protein that deposit methyl groups on genes to turn them off or “silence” them.

Next, the researchers utilized a laser beam to generate damage to the DNA in the colon cancer cell lines. Once more, CHD4 along with its crew of repair proteins descended quickly into the damage site.

“This results suggests that the presence of CHDR and its accompanying proteins may be part of a universal system for repairing DNA damage,” says Stephen B. Baylin M.D., the associate director for research programs at the Kimmel Cancer Center. Validating the idea, the researcher prevented cells from creating CHD4 by genetically disrupting the gene, the repair crew of proteins did not even appear after exposure to the laser or hydrogen peroxide.

The research team notes that the type of gene kept switched off could very well be associated to cancer. A discovery of eight genes that could be already methylated and consequently switched off in the colon cancer cells is considered to be likely tumor suppressors. Upon further examination, it was revealed that these genes were already enriched with CHD4. When the scientists stopped the cells from creating CHD4, they became reactivated and lost their methylation, therefore able to generate proteins that stopped the spread of cancer cells.

According to the Cancer Genome Atlas, a National Institutes of Health database that categorizes genetic mutations that are considered to be cancer risk factors, lung, colon and other forms of cancers – between 30 and 40 percent – have higher levels of CHD4 than healthy tissues.

To determine why CHD4 is attracted to the DNA damage site, the researchers searched for other factors. They discovered that CHD4 collaborates directly with 8-oxoguaine glycosylase (OGG1), an enzymes that removes guanine – one of the many units that make up DNA – when it becomes damaged. When the enzyme was removed from cells, CHD4 did not arrive at specific parts of the damaged DNA.

The DNA of colon cancer cells were color stained to determine the most probable positions of OGG1. The researchers discovered the enzyme at the same locations as the eight tumor suppressor genes, which are frequently switched off when cancer occurs.

“Taken together,” Baylin says, “our experiments suggest that CHD4 and the resulting methylation is a really important phenomenon associated with the cause of colon and probably many other cancer types.”

The study was published in the in the journal Cancer Cell on May 8, 2017.

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