Enzyme Complex Thought To Promote Cancer Development Can Also Help Prevent It

In the Oct. 14 issue of Science, researchers report that thebiomarker in question - an enzyme known as EZH2 - leads a duplicitouslife. In its "native" state, the enzyme acts as a suppressor for cancercell growth that works to inhibit cancer development. But when it isphosphorylated (when a phosphate group is added to the molecule), itturns vicious and acts to promote oncogenesis.

The researchers found the two forms of EZH2 after theyidentified the "switch" that leads to its phosphorylation - thewell-known culprit Akt, an enzyme that has already been associated withcancer development.

The findings explain not only why high levels of EZH2 (when bound toits partner proteins, such as EED) have been shown to identify peoplewho have an aggressive, metastatic form of breast or prostate cancer,but also why elevated levels of EED appear to offer protective effectsagainst virulent lymphoma.

"This has become a big riddle to cancer researchers who want tobe able to use EZH2 as a marker upon which to base aggressivetreatment," says the study's lead author, Mien-Chie Hung, Ph.D., chairof the Department of Molecular and Cellular Oncology. "We now knowthere are two different forms of EZH2. The phosphorylated one enhancesoncogenesis, whereas the nonphosphorylated EZH2 works to inhibit cellgrowth."

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 bothkinds of EZH2 that has been measured in previous biomarker studies)since it is the one with oncogenic properties and appears to helpcancer cells invade nearby tissue, he says. "We need more study todetermine this, but my prediction is that this form may be a bettermarker because it enhances the growth of cancer cells and tumors," hesays.

The second is that the researchers developed a "mutant" proteinthat stops EZH2 from being phosphorylated, and they say this moleculemight provide the basis for either a small-molecule drug or a genetherapy treatment, Hung says. Indeed, in their study, the research teamused the agent to reduce tumor growth in a mouse model of human breastcancer. "We believe that identifying small molecules that could switchbetween the phosphorylated and nonphosphorylated EZH2 form may providea screening strategy for cancer treatment," he says.

Finally, the study demonstrates the power of researching whatis known as "epigenetics" molecular mechanisms in cancer - the notionthat genes and their protein products do not have to be mutated for thedisease to develop. In this field of study, researchers look at howbeneficial genes/proteins may be silenced by molecules that help handleDNA.

For example, one area of active investigation is the power thathistones exert on gene expression. Histones are nature's way ofphysically controlling unwieldy "naked" DNA by compacting it. Butscientists now know that histones themselves can be modified byphosphorylation, as well as through another process known asmethylation, in which one atom on a biological molecule is replaced bya different set of chemicals. Histone methylation, in particular, isnow regarded as a strong modifier of genetic activity, and can work toeither activate or silence gene expression.

The M. D. Anderson researchers conclude that Akt regulates theability of EZH2 to silence genes that are needed to protect againstcancer development. When Akt is activated, it phosphorylates EZH2,making it break free from a particular histone known as H3. If it isnot bound to H3, EZH2 cannot methylate H3, thus these silenced genes(which are believed to be oncogenes) are re-expressed. If Akt is notactivated, it does not phosphorylate EZH2, and this enzyme remainsbound to and methylates H3, allowing it to silence gene expression.

"Our results imply that Akt regulates the methylation activitythrough phosphorylation of EZH2, which may contribute to oncogenesis,"Hung says.

The study was funded by the National Institutes of Health. In additionto Hung, the study co-authors include: Tai-Lung Cha, M.D., Ph.D.;Binhua P. Zhou, M.D., Ph.D.; Weiya Xia, M.D.; Yadi Wu, Ph.D.;Cheng-Chieh Yang, D.D.S.; Chun-Te Chen; Bo Ping, Ph.D.; and Arie P.Otte, Ph.D. Cha was partially supported by the Tri-Service GeneralHospital, Taiwan.