Assistant Professor of Oncology
Consultant in Oncology and Investigator at Johns Hopkins Singapore
Dr. Hsieh practices with Johns Hopkins Singapore in the Tan Tock Seng Hospital in Singapore. His specialties are Lymphomas and Head and Neck cancers.
Molecular Pathogenesis of Epstein-Barr Virus (EBV)EBV is a ubiquitous herpes virus associated with a variety of tumors, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), nasal lymphoma, posttransplant lymphoma, Hodgkin’s disease, and AIDS-lymphoma. EBV is a transforming virus and can immortalize B-cells and cause lymphoma in various animal models. Virtually all NPC harbors EBV, regardless of geographic distribution, ethnic origin and the local prevalence of the disease. The presence of EBV in NPC provides us with a novel diagnostic and therapeutic target.
Dense CpG methylation silences the transcription of EBV promoters and plays an important role in the regulation of EBV latency. The EBV promoters driving immunodominant viral proteins are suppressed by hypermethylation in tumors, and thus EBV can escape from host immune surveillance. This suppression is reversible by treatment with demethylation drugs such as 5-azacytidine and can be developed as a therapeutic strategy.
Epigenetics of Nasopharyngeal Carcinoma (NPC)Carcinogenesis is a multistep process and involves the disruption of multiple genes by either genetic or epigenetic mechanisms. NPC is a major tumor killer for Chinese in Southeast Asia. It is the fifth most common tumor in males in Singapore. Both environmental (such as EBV) and genetic/epigenetic factors have been suggested to contribute to its pathogenesis. Aberrant hypermethylation of tumor suppressor gene (TSG) promoters can silence their expression, resulting in the loss of TSG functions and contributing to tumorigenesis. Pharmacological demethylation of TSG promoters can activate TSG expression and restore TSG functions. We intend to identify new TSG candidates that are inactivated by hypermethylation in NPC, by using various subtractive, cancer genomics and microarray analyses. We further aim to study the regulation and functions of these genes and use them to develop molecular diagnostic and therapeutic strategies toward this tumor.
We are also interested in fundamental epigenetic study, such as the aberrant methylation in DNA methyltransferase (DNMT)-deficient ICF cells and somatic cells, and the identification of new DNMT homologues.
Murray, P. G., Qiu, G. H., Fu, L., Waites, E. R., Srivastava, G., Agathanggelou, A., et al. 2004. Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma. Oncogene 23:1326-1331.
*Chan, A., *Tao, Q., Robertson, K. D., Flinn, I. W., Mann, R.B., Klencke, B., et al. 2004. Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors in patients. J. Clin. Oncol. 22:1373-1381. [* co-first authors]
Ying, J., Srivastava, G., Gao, Z., Zhang, ,X., Murray, P., Ambinder, R., & Tao, Q. 2004. Promoter hypermethylation of the cyclin-dependent kinase inhibitor (CDKI) gene p21WAF1/CIP1/SDI1 is rare in various lymphomas and carcinomas. Blood 103:743-746.
Qiu, G. H., Tan, L. K., Loh, K. S., Lim, C. Y., Srivastava, G., Tsai, S. T., Tsao, S. W., & Tao, Q. 2004. The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma. Oncogene 23:4793-4806.
Lim, C. Y., Ambinder, R. F., Tan, L. K. S., Loh, K. S., Murray, P. G., Swinnen, L. J., et al. Constant epigenetic silencing of the 5'-most W promoter of Epstein-Barr virus, Wp1, in carcinomas and lymphomas including posttransplant lymphoma. (submitted)
Chen, W., Wu, J., Soo, R. A., Tao, Q., Putti, T., Tan, K.B., et al. Celecoxib coordinately regulates multiple genes involved in the initiation of mRNA translation. (submitted)