Scientists from A*STAR's Genome Institute of Singapore (GIS) and the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore came together to understand how EZH2, a cancer-promoting gene which is known to be involved in many types of cancers, is activated in breast cancer and lymphomas. The collaborative discoveries have been published in the journals, PNAS and Blood, respectively. The new findings pave the way to develop more effective treatment strategy for aggressive cancers associated with EZH2.
Identifying new pathway of tumour-promoting EZH2 may lead to targeted therapies for aggressive breast cancer.
It is known that Polycomb repressive complex 2 (PRC2) and its catalytic component EZH2 are often overexpressed in multiple human malignancies, which promotes cancer. Interestingly, EZH2 or PRC2 also has a protective role against tumour formation in certain cancer types, including solid tumours and blood cancers. However, it is unclear how this paradoxical role of EZH2/PRC2 - as a tumour-promoting and tumour-suppressing gene - is regulated in cancer.
Researchers at the GIS, led by Prof Qiang Yu, found that the paradoxical role of EZH2/PRC2 in breast cancer can be switched when tumour cells are in hypoxic condition, a situation when fast growing solid tumour cells have been deprived of oxygen. The researchers found that when the tumour cells are supplied with sufficient oxygen, EZH2/PRC2 acts as a tumour suppressor to inhibit some of the genes involved in cancer invasion. However, this protective function against cancer progression is attenuated by hypoxia-inducible factor 1-alpha (HIF1-alpha), which is activated during hypoxia. Instead, EZH2 engages another well-known tumour-promoting gene, FoxM1, to promote breast cancer invasion and this function no longer needs the catalytic function of EZH2. This study was published in PNAS in June 2016.
"Interestingly, this phenomenon seems to be more common in triple negative breast cancer (TNBC), as compared to other types of breast cancer," said Prof Yu, the study's co-corresponding author and Senior Group Leader, Cancer Therapeutics & Stratified Oncology at the GIS. "We were among the first in the world to show a non-catalytic function of EZH2 in cancer a few years ago. Now that we identified a new pathway of EZH2 in promoting TNBC invasion, this finding may lead to a new treatment strategy to target TNBC, a disease in which effective treatments are currently lacking."
Prof Wee Joo Chng, co-corresponding author of the study, and Deputy Director and Senior Principal Investigator at CSI Singapore, added, "The study fundamentally changes our understanding on the role of EZH2 in breast cancer. Apart from providing molecular insights into how EZH2/PRC2 is regulated in the tumour microenvironment, it also provides therapeutic implications: without a proper patient stratification, the catalytic inhibitor of EZH2 treatment may exacerbate the disease progression."
In a separate study on natural killer/T-cell lymphoma, a relatively rare lymphoma that is more common in Asia, the researchers found that EZH2 activity is regulated by a protein kinase called JAK3. Phosphorylation of EZH2 by JAK3 leads to dissociation of EZH2 from PRC2 complex, leading to a non-catalytic activity of EZH2 to promote cancer cell proliferation. Published in Blood in June 2016, the study was led by Prof Chng, whose team focuses on hematological oncology.
"As JAK3 is often mutated and activated in natural killer/T-cell lymphoma cells, this finding is particular intriguing as it suggests a predominant non-catalytic function of EZH2 in JAK3 mutant natural killer/T-cell lymphoma. Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer," said Prof Chng, who is also Director of the National University Cancer Institute, Singapore (NCIS).
Together, these studies in both solid tumours and blood cancers raise concerns on the therapeutic application of EZH2 catalytic inhibitors, which are currently under active clinical development. Prof Chng added, "Moving forward, a biomarker strategy might be needed to ensure appropriate application of EZH2 inhibitors. This will help to identify tumours where EZH2 requires its catalytic activity or actually acting through non-catalytic function. At the same time, we need to develop therapies that can target the non-catalytic function of EZH2."
GIS executive director Prof Huck Hui Ng said, "Findings like these highlight the importance of sustained collaborative research efforts within our community. Deeper insights into these aggressive cancers associated with EZH2 will help us better understand their progression, and in turn, open up new possibilities for more targeted therapies for the patients."
JAK3 activation leads to phosphorylation (a type of protein modification) of EZH2. This phosphorylation event shifts EZH2 from its normal function of suppressing the expression of genes to a new function of activating genes which lead to the development of NK lymphoma. This study suggests that the use of JAK3 inhibitors can block EZH2 phosphorylation in NK lymphoma and lead to the killing of NK lymphoma cells.