Beat enzyme, curb cancer: study

AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH SINGAPORE

Targeting the EZH2 enzyme paves the way to treat the most aggressive form of breast cancer. Image: ideabug/iStockphoto Scientists from the Genome Institute of Singapore (GIS), an institute of the Agency for Science, Technology and Research (A*STAR), and their colleagues at the National University of Singapore (NUS), have uncovered a new way to target EZH2, an enzyme that promotes the estrogen receptor-negative breast cancer, a type of breast cancer that is aggressive and unresponsive to current forms of treatment. This discovery, published in the journal Molecular Cell, paves the way to develop more effective treatment strategy for aggressive breast cancers associated with EZH2. It has been known that EZH2 enzymatic activity promotes cancer by inactivating some important tumor suppressors, which function as “brakes” to stop tumor growth. Over-expression of EZH2 is often linked to aggressive and rapid spread of breast cancers, the most common cancer in women all over the world. Therefore, EZH2 is an ideal target for breast cancer treatment. For a long time, pharmaceutical companies have focused on developing drugs to block EZH2 enzyme activity so that tumor suppressors can perform their protective role in blocking cancer growth. The team, led by GIS Senior Group Leader Dr Qiang YU, discovered that besides inhibiting tumor suppressor genes through its enzymatic activity, EZH2 is also able to promote cancer through the activation of specific genes involved in the well-known cancer pathway, called NF-kB that is associated with the aggressive estrogen receptor-negative breast cancer. These genes include inflammatory cytokines such as IL6 and IL8 which have important roles in breast cancer progression and cancer stem cell self-renewal. In fact, the team led by Dr Yu discovered that the latter gene-activating function of EZH2 does not require its enzyme activity. “This work suggests that EZH2 may confer its oncogenic role in cancer not just through its gene silencing function of the tumor suppressors but also through its gene activation function of NF-kB pathway,” said Dr Yu. “This new understanding on how EZH2 works as a cancer-causing gene in breast cancer has important therapeutic implication, the results suggest that small molecule drugs that block enzyme activity of EZH2 may not work for cancers caused by EZH2’s activation genes in NF-kB pathway.” Assoc Prof Chng Wee Joo, a clinician scientist working on hematological oncology from the Cancer Science Institute at the NUS commented “This work has important clinical implications. EZH2 is currently thought to cause cancer through its enzymatic activity, hence inhibitors being developed mostly target EZH2’s enzymatic activity. This study from Dr Yu's group demonstrates that the oncogenic effect of EZH2 is cell context dependent and may not always be dependent on its enzymatic activities. This should prompt a re-think in our therapeutic strategies.” “Moving forward,” added A/P Chng, “we should develop biomarkers that will either allow us to identify tumors where EZH2 is predominantly acting through its enzymatic function as a histone methytransferase, inhibiting the protective role of tumor suppressor genes, or where EZH2 is predominantly acting through activation of genes involved in other oncogenic pathways. This will ensure that the appropriate therapeutic strategy can be applied. Alternatively, we should design therapies that will shut down EZH2 completely and not just inhibit its enzymatic function. While this study is conducted in breast cancer, the current findings are likely to have broader implications for cancer therapy in general as EZH2 is deregulated across many types of cancer.” The research findings can be found in the 2 September, 2011 advance online issue ofMolecular Cell under the title “Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers”.