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.
Finally, the study demonstrates the power of researching what is known as "epigenetics" molecular mechanisms in cancer - the notion that genes and their protein products do not have to be mutated for the disease to develop. In this field of study, researchers look at how beneficial genes/proteins may be silenced by molecules that help handle DNA.
For example, one area of active investigation is the power that histones exert on gene expression. Histones are nature's way of physically controlling unwieldy "naked" DNA by compacting it. But scientists now know that histones themselves can be modified by phosphorylation, as well as through another process known as methylation, in which one atom on a biological molecule is replaced by a different set of chemicals. Histone methylation, in particular, is now regarded as a strong modifier of genetic activity, and can work to either activate or silence gene expression.
The M. D. Anderson researchers conclude that Akt regulates the ability of EZH2 to silence genes that are needed to protect against cancer development. When Akt is activated, it phosphorylates EZH2, making it break free from a particular histone known as H3. If it is not bound to H3, EZH2 cannot methylate H3, thus these silenced genes (which are believed to be oncogenes) are re-expressed. If Akt is not activated, it does not phosphorylate EZH2, and this enzyme remains bound to and methylates H3, allowing it to silence gene expression.
"Our results imply that Akt regulates the methylation activity through phosphorylation of EZH2, which may contribute to oncogenesis," Hung says.