Scientists discover new pathways leading to cancer progression
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 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-α (HIF1-α), 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.
“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.”
National University of Singapore news.nus.edu.sg/press-releases/10639-ezh2-breast-cancer-lymphomas
