new way of EZH2 gene identification can lead to targeted therapies against aggressive breast cancer

new way of EZH2 gene identification can lead to targeted therapies against aggressive breast cancer -

Scientists from A * STAR Genomics Institute of Singapore (GIS ) and the Singapore Institute of cancer sciences (CSI Singapore) at the national University of Singapore have come together to understand how EZH2, a gene that promotes cancer is known to be involved in many types of cancers, is activated in the breast cancer and lymphoma. Collaboration The findings were published in the journals, PNAS and blood, respectively. The new findings open the way to develop a more effective treatment strategy for aggressive cancers associated with EZH2.

Invasive breast cancer cells

Identification new way of EZH2 tumor promotion can lead to targeted therapies against aggressive breast cancer

It is known that Polycomb 2 repressive complex (PRC2) and EZH2 catalyst component are often overexpressed in many human malignant tumors, which promotes cancer. Interestingly EZH2 or PRC2 also has a protective role against the formation of tumors in certain types of cancer, including solid tumors and blood cancers. However, it is unclear how this paradoxical role of EZH2 / PRC2 - like a tumor-promoting and tumor suppressor gene -. Is regulated in cancer

Researchers GIS, led by Professor Qiang Yu, found that the paradoxical role of EZH2 / PRC2 in breast cancer can be activated when the tumor cells are in a hypoxic state , a situation where the rapidly growing solid tumor cells were deprived of oxygen. The researchers found that when 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 protection function against cancer progression is attenuated by a factor 1-alpha inducible by hypoxia (HIF-1-alpha), which is activated upon hypoxia. Instead, EZH2 commits another well-known tumor-promoting gene, FoxM1, promote breast cancer invasion and this function does not need the catalytic function of EZH2. This study was published in PNAS in June 2016.

"Interestingly, this phenomenon seems to be more frequent in triple-negative breast cancer (TNBC), compared with other types of breast cancer" , said Professor Yu, co-corresponding author of the study and Senior group leader, cancer Therapeutics & laminated oncology at SGI. "We were among the first in the world to show a non-catalytic function of EZH2 in cancer there a few years ago. Now that we have identified a new way of EZH2 in promoting the invasion TNBC, this finding may lead to new treatment strategy for targeting. TNBC, a disease in which effective therapies are currently lacking "

Prof Chng Wee Joo, co-corresponding author of the study and deputy director and senior principal researcher at CSI Singapore, added:

study fundamentally changes our understanding of the role of EZH2 in breast cancer. In addition to providing a molecular insight on how EZH2 / PRC2 is regulated in the tumor microenvironment, it also provides therapeutic implications :. Without adequate patient stratification, treatment of EZH2 catalytic inhibitor may exacerbate disease progression

Gain a deeper insight into the role of EZH2 in lymphomas

in a separate study of the natural killer cell lymphoma / T cells, a relatively rare lymphoma is more common in Asia, the researchers found that EZH2 activity is regulated by a protein kinase called JAK3. EZH2 by phosphorylation of JAK-3 leads to the dissociation of EZH2 PRC2 complex, leading to a non EZH2 catalytic activity to promote cell proliferation of cancer. Published in the blood in June 2016, the study was conducted by Professor Chng, whose team is focused on hematological oncology.

"As JAK3 is often mutated and activated in lymphoma cells natural killer / T-cells, this finding is particularly intriguing because it suggests a non-catalytic function predominantly of EZH2 JAK3 lymphoma natural killer mutant / T -cell. Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer, "said Professor Chng, who is also director of the National Institute of cancer University, Singapore ( NCIS).

Together, these studies in both solid tumors and blood cancers raise concerns about the therapeutic application of catalytic inhibitors EZH2, which are currently under active clinical development. Prof Chng added:

Moving forward, a biomarker strategy may be needed to ensure proper application of inhibitors of EZH2. This will help identify tumors that EZH2 requires its catalytic or actually acting through non-catalytic function activity. . 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 collaborative research efforts supported within our community. a deeper understanding of these aggressive cancers associated with EZH2 will help us better understand their progress, and in turn, open up new possibilities for more targeted therapies for patients.

switch according EZH2 in natural killer / T-cell lymphoma (NK lymphoma). the activation of JAK-3 leads to phosphorylation (a protein modification type) of EZH2. This phosphorylation event EZH2 moves from its normal function of suppression of gene expression in a new gene activation function which lead to the appearance of a NK lymphoma. This study suggests that the use of JAK3 inhibitors can block EZH2 phosphorylation in NK lymphoma and lead to the destruction of NK cell lymphoma.