Zijie Sun

Current Research Interests

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 action of the androgen receptor (AR) in development and related human diseases. The AR is a nuclear hormone receptor and plays a critical role in the development and maintenance of male characteristics, the growth of normal prostate, and the initiation and progression of prostate cancer. Most prostate cancer cells express the AR and are androgen-dependent. Therefore, androgen ablation therapy has been routinely used for treatment of advanced prostate cancer. While the treatment initially achieves dramatic therapeutic response, it eventually fails in nearly all patients. Consequently, the patients develop castration resistant prostate cancer (CRPC) after two to three years following the therapy, for which there is no curable treatment. Our current efforts mainly focus on several different but closely related areas in androgen signaling and prostate cancer initiation and progression.

Multiple lines of evidence have shown a critical role of AR in ligand-independent prostate cancer cell growth, which implies that androgen-independent cells may still be “AR dependent” and that the AR can be used as a therapeutic target for future treatment. However, there is no appropriate animal model that can be used to evaluate ligand-independent AR action during the course of prostate cancer progression. Most previous GEM models for study of androgen action and prostate tumorigenesis were generated using the probasin promoter, an androgen-inducible promoter. Several ongoing projects in the lab are to generate relevant mouse models that can be used to directly recapitulate the critical role of AR during the course of disease progression. These mouse models are also important for future drug development.

Although nuclear hormone receptors in general are ligand-dependent transcriptional activators, their roles in transcriptional repression have also been studied. We have previously identified a ligand induced AR repression on c-Met expression in prostate cancer cells. Because activation of c-Met induces prostate cancer invasion, metastasis, and hormonal refractoriness, our finding of the AR as a dual transcriptional activator and repressor in prostate cancer cells implies a novel molecular mechanism for prostate cancer progression and CRPC development. While the current androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR, it also attenuates the repressive role of the AR on c-Met expression. Currently, we are using both in vitro and in vivo approaches to address several outstanding questions regarding the molecular basis for AR repression of c-Met expression in androgen sensitive prostate cancer cells, and the mechanisms by which the AR loses this role in castration-resistant tumors.

AR-mediated transcription is facilitated through direct or indirect interactions with different signaling pathways and co-regulators. Emerging evidence suggests a promotional role of the Wnt/beta-catenin signaling pathway in prostate tumorigenesis. Our previous data demonstrated the interaction between the AR and beta-catenin. Since mutations in beta-catenin and other components of the beta-catenin destruction complex are rare in prostate cancer cells, the molecular mechanisms underlying beat-catenin oncogenic activation in prostate cancer may be different from those observed in human colorectal cancer or other malignancies. Several ongoing projects in the lab are focused on the role and regulation of Wnt/beta-catenin signaling and its interaction with the AR in prostate cancer cells.