The 2nd September issue of the journal Molecular Cell has published a discovery that opens the door for the development of more effective treatment strategies for aggressive breast cancers associated with EZH2, an enzyme that promotes the estrogen receptor-negative aggressive breast cancer, which remains unresponsive to current treatment strategies.

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 now uncovered a new way to target EZH2. Research has already established that EZH2 enzymatic activity promotes cancer by inactivating some important tumor suppressors, that function as inhibitors, to stop tumor growth. Over-expression of EZH2 is often associated with aggressive and rapid spread of breast cancers, worldwide the most common form of cancer in women, hence making EZH2 the ideal target for breast cancer treatment.

Pharmaceutical companies have spent a long time concentrating on the development of drugs that block EZH2 enzyme activity to allow tumor suppressors to perform their protective role of blocking cancer growth.

GIS Senior Group Leader Dr Qiang YU and his team unearthed, that apart from inhibiting tumor suppressor genes through its enzymatic activity, EZH2 also promotes cancer by activating specific genes involved in the well-known cancer pathway, named NF-kB, which is linked to the aggressive estrogen receptor-negative breast cancer.

These genes include inflammatory cytokines such as IL6 and IL8, which play an important part in breast cancer progression and cancer stem cell self-renewal. Dr Yu also discovered that the latter gene-activating function of EZH2, does not require its enzyme activity.

Dr Yu explains:

“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. 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.”

In a comment, Assoc. Prof Chng Wee Joo, a clinician scientist working on hematological oncology from the Cancer Science Institute at the NUS said:

“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.”

He concluded his statement saying:

“Moving forward, 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.”

Written by Petra Rattue