In a case of basic science detective work, researchers at The University of Texas M. D. Anderson Cancer Center have solved the puzzle of the "inconsistent biomarker" and, in the process, may have discovered an agent that can suppress cancer development.
In the Oct. 14 issue of Science, researchers report that the biomarker in question - an enzyme known as EZH2 - leads a duplicitous life. In its "native" state, the enzyme acts as a suppressor for cancer cell growth that works to inhibit cancer development. But when it is phosphorylated (when a phosphate group is added to the molecule), it turns vicious and acts to promote oncogenesis.
The researchers found the two forms of EZH2 after they identified the "switch" that leads to its phosphorylation - the well-known culprit Akt, an enzyme that has already been associated with cancer development.
The findings explain not only why high levels of EZH2 (when bound to its partner proteins, such as EED) have been shown to identify people who have an aggressive, metastatic form of breast or prostate cancer, but also why elevated levels of EED appear to offer protective effects against virulent lymphoma.
"This has become a big riddle to cancer researchers who want to be able to use EZH2 as a marker upon which to base aggressive treatment," says the study's lead author, Mien-Chie Hung, Ph.D., chair of the Department of Molecular and Cellular Oncology. "We now know there are two different forms of EZH2. The phosphorylated one enhances oncogenesis, whereas the nonphosphorylated EZH2 works to inhibit cell growth."
Their findings are important for a number of different reasons, says Hung.
The first is that phosphorylated EZH2 may provide a much better "biomarker" of aggressive cancer than "total" EZH2 (the sum of both kinds of EZH2 that has been measured in previous biomarker studies) since it is the one with oncogenic properties and appears to help cancer cells invade nearby tissue, he says. "We need more study to determine this, but my prediction is that this form may be a better marker because it enhances the growth of cancer cells and tumors," he says.
The second is that the researchers developed a "mutant" protein that stops EZH2 from being phosphorylated, and they say this molecule might provide the basis for either a small-molecule drug or a gene therapy treatment, Hung says. Indeed, in their study, the research team used the agent to reduce tumor growth in a mouse model of human breast cancer. "We believe that identifying small molecules that could switch between the phosphorylated and nonphosphorylated EZH2 form may provide a screening strategy for cancer treatment," he says.