Role of Transcriptional Corepressor CtBP1 in Prostate Cancer Progression

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer and the second leading cause of cancer death for men in the United States. The molecular etiology of this disease varies widely and current therapies have a significant failure rate for advanced metastatic disease. A better understanding of the underlying molecular events that regulate prostate cancer progression will significantly enhance our ability to more accurately diagnose, classify and treat prostate cancer patients. By examining the molecular pathways that are dysregulated in cancer cells compared to normal cells, we can identify the specific genetic lesions that drive cancer progression. These genetic lesions can then be targets for appropriate therapies, either with existing compounds or inform the development of novel drugs. Our initial work found that the transcriptional corepressor CtBP1 is overexpressed in aggressive prostate cancer and data suggest that CtBP1 is required for prostate cancer cell survival. Loss of CtBP1 in cancer cells inhibits cell proliferation and invasion in vitro as well as metastasis in vivo. These observations indicate that prostate cancer cells may be critically dependent on CtBP1 for survival. The underlying hypothesis of this study is that CtBP1 may be an important biomarker for aggressive prostate cancer at the time of diagnosis that could impact the clinical management of patients. Being a functional dehydrogenase enzyme, CtBP1 serves as a viable therapeutic target in cancer and inhibition of CtBP1 activity by existing or novel compounds can potentially be used to effectively treat sub-sets of prostate cancer patients. The specific aims of this proposal are: Aim 1. Characterize CtBP1 expression and localization in prostate cancer. The expression of CtBP1 will be evaluated in a large cohort of prostate cancers to test the utility of CtBP1 expression as a diagnostic and prognostic marker. Aim 2. Evaluate the functional role of CtBP1 in aggressive prostate cancer. This aim will provide insight into the role of CtBP1 in prostate cancer progression. In addition, this aim will provide possible avenue to target CtBP1 for therapeutic interventions. Aim 3. Identify and characterize binding partners and targets of CtBP1 that play a role in prostate cancer progression. A sub aim here will focus on identification CtBP1 binding proteins that may be essential for CtBP1 activity and identify cellular proteins that target CtBP1 to the cytosol. Additionally, we will evaluate the genes regulated by CtBP1 followed by biological validation with an emphasis on therapeutically relevant targets. In sum, this proposal will investigate CtBP1 expression and cellular localization as well as determine its functional role in tumor invasion and metastasis. Proposal also identifies the binding partners and downstream targets of CtBP1. Additionally, we will investigate its clinical potential in the diagnosis and prognosis of prostate cancer, and we anticipate that uncovering CtBP1's role in prostate cancer will aid in the identification and/or development of potential inhibitor for treatment.