In a study published in the Sept 2 issue of the journal Molecular Cell, researchers reveal that a novel discovery has paved the way for the development of more effective treatment therapies for EZH2-associated aggressive breast cancers. Estrogen receptor-negative aggressive breast cancer, which continues to remain unresponsive to current treatment strategies, is promoted by the enzyme EZH2.
A new technique to target EZH2 has been discovered by 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). Established research suggests that through its enzymatic activity, EZH2 supports cancer progression by the deactivation of certain significant tumor suppressors, which play a role in inhibiting tumor growth. When EZH2 is excessively expressed, it leads to the aggressive and rapid proliferation of breast cancer, the most widespread form of cancer in women globally. Therefore, EZH2 becomes the perfect target for breast cancer treatment.
In order to facilitate the activity of tumor suppressors in their protective role of blocking cancer growth, drug developers have spent ample time focusing on the development of those drugs that can restrict the activity of EZH2.
According to another astonishing discovery by GIS Senior Group Leader Dr Qiang YU and his team, EZH2 not only restricts tumor suppressor genes through its enzymatic activity, but also encourages cancer progression by triggering particular genes of the familiar cancer pathway, known as NF-kB that is associated with the aggressive estrogen receptor-negative breast cancer.
Inflammatory cytokines such as IL6 and IL8, included in these genes, have a significant role in breast cancer advancement and cancer stem cell self-renewal. According to Dr Yu, EZH2 enzymatic activity is not essential for the latter gene-activating function.
“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,” explains Dr Yu.
Clinician scientist working on hematological oncology from the Cancer Science Institute at the NUS, Assoc. Prof Chng Wee Joo, 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.”
To conclude, he said, “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.”