The Laboratory of Molecular Pharmacology focuses on cancer therapeutics. Cancer is a complex disease and the malignant phenotype involves extensively rewired pathways for growth advantage and survival due to multiple genetic and epigenetic changes. The complexity of alterations in cancer presents a daunting problem with respect to treatment: the malignant process involves multiple aberrant compensatory signaling routes that bypass the inhibition of individual. In addition, cancer is a genetic moving target capable of mutating into resistant or more aggressive forms. Thus, a key to successful therapy is to identify the critical nodes in the oncogeneic network and to target them to reverse cancer phenotypes by inducing apoptosis, senescence and differentiation. In order to generate this system failure in cancer, the most effective approach is probably through the combinational application of a relatively small number of drugs through system perturbation.
We are leveraging various technologies to understand the fundamental questions concerning cancer cell death and survival. Integrating functional genomics, chemical combinations and molecular biology, we are exploring systems biology approach to identify key elements that are critical to a relevant biological phenotype, to identify synthetic lethal gene-gene interactions and to develop novel strategies for cancer therapy.
Damage Response, Cell Cycle Checkpoint and Apoptosis:The majority of therapeutic agents cause DNA damage response, leading to activation of cell cycle checkpoint or apoptosis. Understanding the signals and mechanisms leading to apoptosis or resistance to apoptosis may allow the development of better regimens for the treatment of cancer. Using both genomics mapping and chemical screening approaches, as well as in collaboration with our technology group, we are interested in identifying the key gene modules that are associated with anticancer drug response and deciphering molecular mechanisms of activity of their products as potential targets for therapeutic modulation (J Bio Chem., 2004, Cancer Res. 2005, Cell, 2006, Cancer Res. 2007, J Bio Chem., 2009).
Novel Therapeutic Approaches Targeting Cancer Epigenetic Processes:My laboratory is also interested in pharmacologic modulation of epigenetic processes in cancer. In particular, we are studying the oncogenic Polycomb-mediated gene silencing activity in cancer and its interplay with histone deacetylation and DNA methylation. We are also developing novel chemical approaches that target histone modifications such as histone methylation and deacetylation, leading to interventions of key cancer pathways and efficient apoptosis induction. We have discovered DZNep and its anlogous as a new class of chromatin modifiing compound that have therapeutic potential (PNAS, 2005; J Bio Chem., 2006, Genes & Devel., 2007, Cancer Cell, 2008, Genes & Devel., 2009, Cell Death and Differentiation, 2009)
|1993-1998||Ph.D. Pharmacology. Queen's University, Kinsgston, Ontario, Canada|
|1988-1991||M.Sc. Chinese Academy of Medical Sciences|
|1980-1985||M.B. Qingdao Medical College|
|2011-||Adjunct Professor, DUKE-NUS Graduate Medical School|
|2011-||Adjunct Professor Department of Physiology, National University of Singapore|
|2011-||Senior Group Leader, Cancer Biology and Pharmacology, Genome Institute of Singapore|
|2009-||Adjunct Associate Professor, Cancer and Stem Cell Biology, DUKE-NUS, Singapore|
|2006-||Adjunct Associate Professor, Department of Physiology, National University of Singapore|
|2006-2010||Group Leader, Cancer Biology and Pharmacology, Genome Institute of Singapore|
|2002-2006||Senior Research Scientist and Principle Investigator, Genome Institute of Singapore|
|2000-2002||Visiting Fellow Advanced Technology Center National Cancer Institute Gaithersburg, MD|
|1998-2001||International Fogarty Fellow Laboratory of Molecular Pharmacology National Cancer Institute Bethesda, MD|
|1991-1993||Research AssociateChinese Academy of Medical Sciences|
Honors and Awards
|1998-2002||International Fogarty Fellowship, National Institute of Health|
|1995-1998||Queen's University Dean's Award|
|1993-1995||Queen's University Graduate Fellowship and tuition bursary|
Committee and Advisory Board
|Present||Associate Editor, Molecular Cancer|
|Present||Editoral Board, International Journal of Biochemistry and Cell Biology|
|2005-2006||Management Advisory Committe, Biopolis Life Science Library|
|2008-2011||Development of small molecule targeting histone methylation by ATAR JCO (600K)|
|2005-2007||Post-translational modification of p53 in human cancer by UCSD-NUS-ASTAR (200K USD)|
|2010||GIS/Z05818 : A biomarker for rapamycin resposne (Filed)|
|2009||PCT/SG2009/000356 : DZNep analogs as anti-cancer agents (Filed)|
|2006||PCT/SG2006/000350 : Methods for Cancer Therapy and Stem Cell Modulation (Filed)|
|2006||PCT/SG2007/000058 : Mothods for senstizing DNA Damage Response: A Potential Target for Cancer Therapy (Filed)|
|2005||PCT/SG2006/000053 : Methods for Assessing Suitability of Cancer Patients for Treatment with Histone Deacetylase Inhibitors (Filed)|
|2004||PCT/SG2005/000223 : Modulation of GSK-3 beta and Method of Treating Proliferative Disorders (Granted)|
- Shuet Theng Lee, Zhimei Li, Zhenlong Wu, Meiyee Aau, Peiyong Guan, R.K. Murthy Karuturi, Yih Cherng Liou and Qiang Yu ."Context-Specific Regulation of NF-kB Target Gene Expression by EZH2 in Breast Cancers". Molecular Cell , 43, 798–810, 2011.
- Qiao Y, Jiang X, Lee ST, Karuturi RK, Hooi SC, Qiang YU "FOXQ1 regulates epithelial-mesenchymal transition in human cancers." Cancer Res, 2011 Apr 15;71(8):3076-86. Epub 2011 Feb 23.
- Feng M, Li Z, Aau M, Wong CH, Yang X, Qiang Yu "Myc/miR-378/TOB2/cyclin D1 functional module regulates oncogenic transformation." Oncogene, 2011 May 12;30(19):2242-51. PMID: 21242960
- Zhenlong Wu, Shuet Theng Lee, Yuanyuan Qiao, Zhimei Li, Puay Leng Lee, Yong Jing Lee, Xia Jiang, Jing Tan, Meiyee Aau, Cheryl Zhi Hui Lim, and Qiang Yu. EZH2 regulates cancer cell fate decision in response to DNA damage. Cell Death Differ , 2011 Nov;18(11):1771-9
- Jing Tan, Puay Leng Lee, Zhimei Li, Xia Jiang, Yaw Chyn Lim, Shing Chuan Hooi and Qiang Yu. B55β-associated PP2A complex controls PDK1-directed Myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell, 18:459-471, 2010
- Xiaojing Yang, Min Feng, Xia Jiang, Zhenlong Wu, Meiyee AAu, Zhimei Li, and Qiang Yu. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes & Development . 2009 23: 2388-2393.
- Wu Z, Zheng SS, Li Z, Qiao YY, Aau MY, and Qiang Yu. Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ. 2010 May;17(5):801-10. PMID: 19893569
- Xia Jiang, Jing Tan, Jingsong Li, Saul Kivimäe, Xiaojing Yang1 Li Zhuang, Puay Leng Lee, Mark TW. Chan, Lawrence Stanton, Edison T. Liu, Benjamin N.R.Cheyette and Qiang Yu. DACT3 is an epigenetic regulator of Wnt/β-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 13:529, 2008. PMID: 18538736
- Jing Tan, Xiaojing Yang, Li Zhuang, Xia Jiang, Wei Chen, Puay Leng Lee, RK Murthy Karuturi, Patrick Boon Ooi Tan, Edison T. Liu and Qiang Yu. Pharmacologic disruption of Polycomb repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes & Development. 2007 21:1050.
- Zhao Y, Tan J, Zhuang L, Jiang Xia, Liu ET and Qiang YU (2005). Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim.
Proc Natl Acad Sci U S A . 102:16090-5. (ZY and TJ contributed equally). PMID: 16243973
Complete Publications List