Discovery of cancer-promoting gene pathways may lead to targeted therapies
Scientists 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 new findings pave the way to develop more effective treatment strategies for aggressive cancers associated with EZH2.
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 tumor formation in certain cancer types, including solid tumors and blood cancers. However, it is unclear how this paradoxical role of EZH2/PRC2 – as a tumor-promoting and tumor-suppressing gene – is regulated in cancer.
Researchers from A*STAR’s Genome Institute of Singapore (GIS), led by Prof.Qiang Yu, found that the paradoxical role of EZH2/PRC2 in breast cancer can be switched when tumor cells are in hypoxic condition, a situation when fast growing solid tumor cells have been deprived of oxygen. The researchers found that when the tumor cells are supplied with sufficient oxygen, EZH2/PRC2 acts as a tumor suppressor to inhibit some of the genes involved in cancer invasion. However, this protective function against cancer progression is weakened by hypoxia-inducible factor 1-alpha (HIF1-alpha), which is activated during hypoxia. Instead, EZH2 engages another well-known tumor-promoting gene, FoxM1, to promote breast cancer invasion and this function no longer needs the catalytic function of EZH2.
“Interestingly, this phenomenon seems to be more common in triple negative breast cancer (TNBC), as compared to other types of breast cancer,” said Yu. “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 JooChng, co-corresponding author of the study 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 tumor 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 Chng, whose team focuses on hematological oncology.
Together, these studies in both solid tumors and blood cancers raise concerns on the therapeutic application of EZH2 catalytic inhibitors, which are currently under active clinical development.
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.”
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