Zijie Sun, M.D., Ph.D.

Zijie (ZJ) Sun, M.D., Ph.D., is a professor in the Department of Cancer Biology and Molecular Medicine and the founding director of the Prostate Cancer Research Program in the comprehensive cancer center. Dr. Sun’s research interest focuses on the molecular mechanisms underlying transcriptional control and cell signaling in development and tumorigenesis. His ongoing projects include using cutting-edge mouse models and other in vivo and in vitro approaches to uncover gene expression and genomic and epigenetic alterations during the course of early cancer development and aging. Recently, his group has developed new mouse models to investigate the effects of androgens in the pathogenesis of prostate cancer and other aging-related disorders.  

Dr. Sun has served on many scientific review panels for the Department of Defense and the National Institutes of Health, as well as other funding agencies in the United States and other nations and has published extensively in his research fields. In his career, he has also devoted significant effort to training and mentoring young scientists. Prior to joining City of Hope, Dr. Sun has was a Professor at Stanford University for 18 years following his postdoctoral training at Harvard Medical School and St. Jude Children’s Research Hospital.

Transcriptional control is a key step in the regulation of eukaryotic gene expression. Our lab focuses on understanding the molecular mechanism of transcription factors that govern the transformation of normal mammalian cells to a neoplastic state. We are especially interested in the biological roles of steroid hormone receptors and their coregulators in development and oncogenesis. We use targeted conditional and inducible mouse models and other cellular and molecular approaches to uncover gene expression and genomic and epigenetic alteration during tumor development and progression, and to functionally analyze the biological significance of these changes in oncogenic transformation. Ongoing projects in the lab are specifically addressing several important and unknown questions regarding the pathogenesis of prostate cancer in order to develop novel therapeutics to target these tumor cells.

Androgen signaling has been implicated as a critical pathway in prostate tumorigenesis. However, there is no appropriate animal model that can be used to evaluate ligand dependent and independent androgen receptor (AR) action during the course of prostate cancer initiation and progression. We developed a unique AR transgenic mouse model, in which the AR expression can be “conditionally” activated in a constitutive and tissue specific manner. We demonstrated that activation of AR transgene expression induces prostatic adenocarcinoma formation in mice, demonstrating an oncogenic role for AR in prostate tumorigenesis. This mouse model can also be used to characterize AR action in the absence of androgens, recapitulating ligand-independent AR effect during prostate cancer progression and castration resistant prostate cancer (CRPC) development.

Although nuclear hormone receptors in general are ligand-dependent transcriptional activators, our bench work has demonstrated a novel role of AR as a transcriptional repressor in c-Met expression, the receptor for HGF/SF. Our finding not only elucidates an aberrant regulation of c-Met expression in prostate cancer cells, but also implicates a novel mechanism by which current androgen ablation therapy induces CRPC development. Using several preclinical models, we demonstrated that combined inhibition of AR and c-Met oncogenic pathways can prevent or delay CRPC development. Our bench works have translated several ongoing clinical trials to test whether adding c-Met inhibitors to current androgen ablation mono-therapy can improve clinical outcomes, which may and delay and prevent CRPC development.

Androgen signaling induced transcription is facilitated through direct or indirect interactions with different signaling pathways and co-regulators. Emerging evidence suggests a promotional role of the Wnt/β-catenin signaling pathway in prostate tumorigenesis. We have demonstrated the interaction between the AR and β-catenin in prostate cancer cells. Because mutations in adenomatous polyposis coli (APC), beta-catenin, and other components of the destruction complex are generally rare in prostate cancers, other mechanisms of aberrant Wnt signaling activation have been speculated. To address these critical questions, we developed several novel mouse models to evaluate the promotional role of androgen signaling in β-catenin initiated oncogenic transformation in prostate cells. The ongoing project will gains innovative information on prostatic stem/progenitor cells, and may lead to new directions to current paradigms in the field.