Singapore A*STAR's GIS researchers find new pathways leading to cancer progression


Researchers from Agency for Science, Technology and Research’s (A*STAR) Genome Institute of Singapore (GIS) and the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore have discovered how EZH2 is activated in breast cancer and lymphomas.

EZH2 is a cancer-promoting gene known to be involved in many types of life-threatening cancers.

The new research results pave way to develop improved treatment strategy for aggressive cancers related to EZH2, particularly aggressive breast cancer.

Polycomb repressive complex II (PRC2) is one of the two classes of polycomb- group proteins and its catalytic component EZH2 is mostly overexpressed in multiple human malignancies, thereby causing cancer progression in the patients.

However, EZH2 / PRC2 also helps protect tumour formation in certain types of cancer, such as solid tumours and blood cancers.

GIS executive director 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.”

The team of GIS scientists, led by professor Qiang Yu, discovered that in the case of breast cancer, the dual role of EZH2 / PRC2 as a tumour-promoting and tumour-suppressing gene can be switched when tumour cells are in hypoxic condition, a situation that occurs when fast growing solid tumour cells are deprived of oxygen.

The researchers discovered that when the tumour cells are provided with sufficient oxygen, EZH2 / PRC2 acts as a tumour suppressor to inhibit some of the genes involved in cancer invasion.

"Findings like these highlight the importance of sustained collaborative research efforts within our community."

The protective function of EZH2 / PRC2 against cancer progression is attenuated by hypoxia-inducible factor I-alpha (HIF1-alpha), which is activated during hypoxia.

EZH2 uses another well-known tumour-promoting gene, FoxM1, in order to promote breast cancer invasion and this function does not require the catalytic function of EZH2.

Another study on T-cell lymphoma is a relatively rare lymphoma more common in Asia, which demonstrates that EZH2 activity is regulated by a protein kinase called JAK3.

Phosphorylation of EZH2 by JAK3 results in dissociation of EZH2 from PRC2 complex, thereby leading to a non-catalytic activity of EZH2 in order to promote cancer cell proliferation.


Image: Invasive breast cancer cells. Photo: courtesy of Genome Institute of Singapore.