Poster abstracts
Poster number 66 submitted by Benjamin Sunkel
Targetable CREB1/FoxA1-driven prognostic gene expression relies on cyclic nucleotide-dependent kinase-mediated MED1 phosphorylation in prostate cancer
Benjamin Sunkel (Ohio State Biochemistry Program), Dayong Wu, Zhong Chen (Department of Molecular Virology, Immunology, and Medical Genetics, the Ohio State University), Zhenqing Ye (University of Texas Health Science Center at San Antonia), Victor X. Jin (University of Texas Health Science Center at San Antonia), Steven K. Clinton (Department of Internal Medicine, College of Medicine, the Ohio State University), Qianben Wang (Department of Molecular Virology, Immunology, and Medical Genetics, the Ohio State University)
Abstract:
Identifying disease-driving transcription factor networks in addition to the androgen receptor in prostate cancer promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of the master transcription factors (TFs) CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines and primary prostate cancer tissues to investigate their role in defining prostate cancer gene expression profiles. We identified a CREB1/FoxA1 up-regulated 19-member cell cycle-related gene Panel A and a CREB1/FoxA1 repressed 6-member putative tumor suppressor gene Panel B which were prognostic of more rapid prostate cancer recurrence independent of clinical prognosticators in Cox proportional hazard models. We also found that these panels improved upon clinical features in predicting future recurrence events via logistic regression. Further analysis of our 19-gene panel revealed that its expression was potentiated by enhanced CREB1 phosphorylation, and we investigated the utility of inhibiting known CREB1-targeting kinases in disrupting this signaling. Rather than reducing CREB1 phosphorylation levels, cyclic nucleotide-dependent protein kinase inhibition reduced the phosphorylation of an important CREB1 coactivator, MED1, resulting in abrogated target gene expression and cell proliferation. We finally asked how accumulating cyclic nucleotide levels impact this signaling axis, and found that phosphodiesterase inhibitor treatment, commonly utilized in managing erectile dysfunction following radical prostatectomy, significantly enhanced cell cycle gene expression and prostate cancer cell proliferation. In total, our findings establish a central role for CREB1 in driving prostate cancer progression, and demonstrate the utility of CREB1/FoxA1 target gene expression levels as a biomarker for identifying at-risk patients that may benefit from trials of adjuvant treatment. Critically, our work also provides a molecular understanding of the risks associated with phosphodiesterase treatment in the prostate cancer setting, supporting epidemiologic studies of their deleterious effect on treatment outcomes.
Keywords: Prostate cancer, CREB1, PDEi