Sze Siu Kwan, Newman
Director of Proteomics Core of Bioscience Research Centre
- Ph.D., University of Hong Kong, Hong Kong, 1990-1995
- B.Sc., University of Hong Kong, Hong Kong, 1987-1990
- 2012.9 - present Associate Professor, Nanyang Technological University, Singapore
- 2006.6 -, Assistant Professor, Nanyang Technological University, Singapore
- 2002.7 - 2006.5, Group Leader, Genome Institute of Singapore, Singapore
- 2003.7 - 2006.5, Adjunct Assistant Professor, National University of Singapore, Singapore
- 2005.5 - 2006.5, Adjunct Assistant Professor, Nanyang Technology University, Singapore
- 2001.5 - 2002.6, Visiting Scientist, Cornell University, USA
- 1998.6 - 2001.5, Postdoctoral Fellow, University of Waterloo, Canada
- 1995.5 - 1998.5, Postdoctoral Fellow, University of Toronto, Canada
Hypoxia Driven Cancer Development
My laboratory conducts cross-disciplinary research that couples proteomics and systems biology with biochemistry, molecular and cellular biology and animal models to uncover novel mechanisms of disease initiation and progression. My experience of multidisciplinary research has allowed me to conduct highly innovative investigations that have culminated in my pioneering studies of hypoxia-induced oncogenesis using advanced proteomic technologies. My lab has uncovered numerous molecular pathways that promote cancer progression in response to hypoxia stress, resulting in a number of high-profile publications that have been extensively cited in the field. While the majority of investigators in this arena are attempting to identify epigenetic marks that can influence cellular gene expression, my lab instead focuses on the study of the chromatin-associated proteome, with the ultimate aim of developing methods of intervening in the epigenetic development of major human disorders. Using this novel approach, we recently discovered several novel hypoxia-sensitive epigenetic regulators (HYSERs) that drive cancer progression in low-oxygen conditions such as those that occur in developing solid tumors. Our most recent paper describing the role of HP1BP3 in hypoxia-driven cancer progression was highlighted in the November 2014 issue of the American Society for Biochemistry and Molecular Biology newsletter ASBMB Today as ‘A new epigenetic target for treating all cancers’.
We are now employing a battery of high-throughput systems biology approaches to define the molecular mechanisms by which these HYSERs regulate cancer cell biology. To do this, we are analyzing HYSER post-translational modifications, identifying their protein complex partners, determining their effects on genome-binding using ChIP-seq, assessing their influence on the epigenome using DNA-methylation profiling, evaluating modulation of the cellular transcriptome using RNA-seq, and investigating changes in the cellular proteome using iTRAQ-LC-MS/MS. By using systems biology approaches to integrate and analyze these data, we aim to uncover the molecular mechanisms that underpin hypoxia-driven cancer development. Having already demonstrated a role for the hypoxia-induced regulator HP1BP3 in tumor progression, we are now conducting new experiments in a novel HP1BP3-knockout transgenic mouse model and determining the 3D structure of the protein to enable the future design of specific inhibitors for potential therapeutic use in cancer patients.
Functional Foods and Bioactive Dietary Compounds for Cancer Chemoprevention
Despite intensive research over recent decades, cancer remains a major cause of death globally. Since cancer is difficult to detect in the early stages and hard to cure in the later stages, the saying that “Prevention is better than cure” is particularly true in the case of cancer. But, how can we prevent cancer? Numerous epidemiological studies now indicate that consumption of certain foods can protect against the risk of developing cancers, and recent lab-based research suggests that these so called ‘functional foods’ can modify the epigenetics of human cells. Understanding how best to use our diet to minimize cancer risk has the potential to confer substantial health benefits to the human population at large, and significantly benefit public health care systems around the globe. We therefore recently embarked on a systems biology study to answer the long-standing question of how food protects against malignancy at a molecular level. We have already observed that prolonged exposure to bioactive dietary compounds derived from soybean and brassica vegetables can stimulate cancer cells to adopt a benign phenotype. We have also discovered several potential ‘diet-sensitive epigenetic regulators’ (DISERs) that could potentially be targeted for cancer chemoprevention. We now aim to use systems biology approaches similar to those employed in our hypoxia cancer study to dissect the molecular mechanism by which DISERs contribute to cancer prevention.
Degenerative protein modifications –Causing Degenerative Diseases and Human Aging
My laboratory is also applying advanced proteomics technology to study the role of degenerative protein modifications (DPMs) in human degenerative diseases using animal models and clinical samples. DPMs are caused by non-enzymatic chemical reactions that induce changes in protein structure and function which promote disease initiation, pathological progression, and also natural ageing. These undesirable DPMs include oxidation, carbonylation, carbamylation, glycation, deamidation, racemerization and many others, which impart deleterious structural and functional changes on extracellular matrix proteins and long-lived cell types such as cardiomyocytes and neurons, leading to impaired overall organ function. Despite the obvious clinical importance of understanding DPM biology, the molecular mechanisms that mediate these modifications and their health impacts remain poorly understood largely due to the technical challenges associated with their study. Recently, we have developed specific mass spectrometry-based proteomics technologies to permit global quantitative proteomic profiling of cell lines, animal models and clinical samples from a variety of different patient types for discovering DPMs. These new methods have not only uncovered changes in global protein expression levels, but have also identified specific modifications of particular amino acid residues in protein backbones that are associated with disease progression. The non-enzymatic induction of DPMs as revealed by proteomic profiling can help us to better understand the underlying molecular pathology of protein dysfunction in neurodegenerative diseases, cardiovascular diseases and natural aging.
Structural modeling of the potential impact of deamidation damaged Na+/K+ ATPase ion channel protein on the ion transport and polarization/depolarization of neuron. The impaired regulation and compromised activity of ion channel proteins contribute to the pathophysiology of vascular dementia.