Hotwiring Cancer-Fighting Genes
Disabling 2 enzymes helps combat colorectal cancer in lab setting
WEDNESDAY, April 3, 2002 (HealthDayNews) -- Gene mutations aren't the only cellular defects that can lead to cancers. Increasingly, scientists are turning their attention to a process call DNA methylation.
And the discovery of two essential enzymes and the role they play in the process should shed more light on the development of cancer.
A new study in tomorrow's issue of the journal Nature reveals that the two enzymes maintain DNA methylation in colorectal cancer cells a process the researchers say may be linked to inactivation of tumor suppressor genes in cancers.
They say the findings could point drug developers toward compounds that can switch on deactivated tumor suppressor genes.
DNA methylation is a process that lets cells determine which genes should be "silenced," without actually changing the gene. During normal development of a cell, this is critical for switching off genes when they aren't needed. However, if it occurs at the wrong time or in the wrong place, it can switch off genes that prevent uncontrolled cell growth, a hallmark of cancer.
"Most gene research in cancer has focused on mutations in genes that make them go awry and cause cancer-promoting processes," says Ina Rhee, study author and a researcher at Johns Hopkins School of Medicine. She adds the tumor-suppressing gene p53 is one of the better-known examples of these mutations.
However, Rhee says experts are now interested in ways that genes can be adversely affected that don't specifically involve mutations.
DNA methylation is one of the possibilities.
"We know observationally that genes that are methylated are often turned off," Rhee says. "Whether that's a cause-and-effect or just a correlation, it's difficult to say."
"Whether it directly turns off the gene or somehow marks it so that other factors come into play and turn it off, that is an unanswered question," Rhee adds. "We know that methylation is a marker of gene inactivity."
The researchers started out with a goal of better understanding how methylation works. They targeted the methylation "machinery" by deleting some the methylating enzymes in cancerous colorectal cells. The role of the enzymes has been poorly understood, Rhee says, although researchers had some clues from a previous study on laboratory mice.
"In a mouse cell, if you take out the enzyme DNMT1, almost all methylation disappears," she says. In a similar experiment in human cells done roughly two years ago, it didn't appear to have the same effect on gene methylation, which left the researchers puzzled.
When researchers removed a different enzyme, DNMT3b, in a culture of human colorectal cancer cells, it reduced methylation by only 3 percent. However, when Rhee and her colleagues removed both the DNMT1 enzyme and the DNMT3b enzyme, methylation was reduced by more than 95 percent.
"It appears now, when you take both of these enzymes away, the cells are drastically demethylated and some of these tumor suppressor genes lose their methylation and turn back on," Rhee says. "It seems that you need both of these enzymes together to achieve that silencing."
Rhee and her colleagues don't yet have a clear understanding of how these enzymes interact with one another. But she notes the colorectal cancer cells used for the project still showed some degree of methylation. One of the next steps, she adds, will be to identify other enzymes that may be responsible for the methylation that remained in the cells.
Rhee says researchers are trying to design compounds that can demethylate genes, with the ultimate goal of turning an inactivated tumor suppressor gene back on.
Ideally, such a therapy could switch a cell from a fast-growing, cancerous state back to normal function.
"[These findings] reinforce the notion that this is something that could be tried," Rhee says.