7 September 2011 -- Scientists from the Genome Institute of Singapore (GIS), an institute of the Agency for Science, Technology and Research (A*STAR), and their colleagues at the National University of Singapore (NUS), have uncovered a new way to target EZH2, an enzyme that promotes the estrogen receptor-negative breast cancer, a type of breast cancer that is aggressive and unresponsive to current forms of treatment. This discovery, published in the journal Molecular Cell, paves the way to develop more effective treatment strategy for aggressive breast cancers associated with EZH2.
It has been known that EZH2 enzymatic activity promotes cancer by inactivating some important tumor suppressors, which function as “brakes” to stop tumor growth. Over-expression of EZH2 is often linked to aggressive and rapid spread of breast cancers, the most common cancer in women all over the world1
Therefore, EZH2 is an ideal target for breast cancer treatment. For a long time, pharmaceutical companies have focused on developing drugs to block EZH2 enzyme activity so that tumor suppressors can perform their protective role in blocking cancer growth. The team, led by GIS Senior Group Leader Dr Qiang YU, discovered that besides inhibiting tumor suppressor genes through its enzymatic activity, EZH2 is also able to promote cancer through the activation of specific genes involved in the well-known cancer pathway, called NF-kB that is associated with the aggressive estrogen receptor-negative breast cancer. These genes include inflammatory cytokines such as IL6 and IL8 which have important roles in breast cancer progression and cancer stem cell self-renewal. In fact, the team led by Dr Yu discovered that the latter gene- activating function of EZH2 does not require its enzyme activity.
“This work suggests that EZH2 may confer its oncogenic role in cancer not just through its gene silencing function of the tumor suppressors but also through its gene activation function of NF-kB pathway,” said Dr Yu. “This new understanding on how EZH2 works as a cancer-causing gene in breast cancer has important therapeutic implication, the results suggest that small molecule drugs that block enzyme activity of EZH2 may not work for cancers caused by EZH2’s activation genes in NF-kB pathway.”
Assoc Prof Chng Wee Joo, a clinician scientist working on hematological oncology from the Cancer Science Institute at the NUS commented “This work has important clinical implications. EZH2 is currently thought to cause cancer through its enzymatic activity, hence inhibitors being developed mostly target EZH2’s enzymatic activity. This study from Dr Yu’s group demonstrates that the oncogenic effect of EZH2 is cell context dependent and may not always be dependent on its enzymatic activities. This should prompt a re-think in our therapeutic strategies.”
“Moving forward,” added A/P Chng, “we should develop biomarkers that will either allow us to identify tumors where EZH2 is predominantly acting through its enzymatic function as a histone methytransferase, inhibiting the protective role of tumor suppressor genes, or where EZH2 is predominantly acting through activation of genes involved in other oncogenic pathways. This will ensure that the appropriate therapeutic strategy can be applied. Alternatively, we should design therapies that will shut down EZH2 completely and not just inhibit its enzymatic function. While this study is conducted in breast cancer, the current findings are likely to have broader implications for cancer therapy in general as EZH2 is deregulated across many types of cancer.”
The research findings described in the press release can be found in the 2 September, 2011 advance online issue of Molecular Cell under the title “Context- Specific Regulation of NF-?B Target Gene Expression by EZH2 in Breast Research publication: Cancers”.
Shuet Theng Lee1,2, Zhimei Li1, Zhenlong Wu1, Meiyee Aau1, Peiyong Guan3, R. K. Murthy Karuturi3, Yih Cherng Liou2,4, and Qiang Yu1,5,6*
Authors:
1 Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
2 Graduate School for Integrative Sciences and Engineering, National University of Singapore
3 Information and Mathematical Science, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
4 Department of Biological Sciences, National University of Singapore
5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore
6 Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore
* Correspondence: yuq@gis.a-star.edu.sg, DID: (65) 6808 8127
About the Genome Institute of Singapore
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine.
The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit www.gis.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR) The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity.
A*STAR supports Singapore’s key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, and with other local and international partners. For more information about A*STAR, please visit www.a-star.edu.sg
For more information, please contact:
Winnie Serah Lim (Ms)
Genome Institute of Singapore
Office of Corporate Communications
Tel: (65) 6808 8013
Email: limcp2@gis.a-star.edu.sg
