VCU news

By Lorraine Cichowski and Shirley Taylor

RICHMOND, Va. – Researchers at Virginia Commonwealth University have discovered a link between a key gene that suppresses the growth of cancer cells and DNA methylation, a process that controls which genes function by turning some genes on and other genes off.

The study, published in the journal Cancer Research, found that the p53 protein, a central tumor suppressor and the most frequently mutated gene in cancer, regulates the enzyme directly responsible for putting small groups of atoms called methyl groups on a person’s DNA. When normal p53 function is lost, as it is in almost half of all cancer patients, DNA methylation activity increases dramatically, the researchers found.  Increased DNA methylating activity has been implicated in altering gene expression in tumors in a way that appears to promote uncontrolled cell division and drive tumor progression.

“p53 has been called the guardian of the genome. It watches out for DNA damage and, when this is detected, p53 stops the cell cycle and activates DNA repair enzymes. If it can’t repair the genome, then p53 signals the cell to die – which is important in control of cancer,” says Shirley M. Taylor, Ph.D., associate professor of microbiology and immunology and director of the Molecular Biology Core Facility at VCU’s Massey Cancer Center. Dr. Taylor was the lead author on the study.

“But p53 also is the most frequently altered gene in human cancers. When that happens, it allows DNA methylation to be elevated, which has the effect of shutting down other growth control genes and contributing to the development of cancers.”

DNA methylation is essential for the normal development and functioning of organisms because it changes the structure of DNA, turning gene expression on or off, up or down, and, therefore, determining which genes the cells use. But abnormal DNA methylation processes have been shown to cause developmental and other diseases, including cancer.

Taylor and her colleagues used human colon cancer cells to study levels of the methylating enzyme, DNA methyltransferase 1. They found that deleting the p53 gene resulted in a six-fold increase in DNA methylation, which they suggested might be sufficient to drive the altered patterns of methylation seen in human cancer.

“We have known for some time that cancer cells have dramatic changes in methylation that silence the expression of genes that control cell growth, called tumor suppressor genes. What has been missing is an understanding of what makes these changes happen.  Losing p53 function seems to be one of the events that drive alterations in DNA methylation,” says Taylor.

The presence of the normal p53 gene in the laboratory experiment caused methylation activity levels to moderate, which Taylor said could be important in development of new anti-cancer drugs. Several companies currently are developing drugs that target methylation.

“Once you reverse the silencing of the control genes, cell growth should come back under control,” Taylor says.

The VCU findings are an important development in the new scientific field of epigenetics, which refers to modifications to genes, other than changes in the DNA sequence itself. These changes can include addition of molecules, including methyl groups, to the DNA backbone. Some studies have linked these modifications to environmental factors, including diet, but scientists still are trying to understand the complicated processes that cause gene expression to change.