Role of E3 Ubiquitin Ligase TRIM25 in Prostate Cancer

Proposed Research: ¬Prostate cancer (PCa) is the second most common cancer in American men and has led to approximately 30K deaths every year. Forkhead box A1 (FOXA1) is a transcription factor whose mutations and aberrant expressions promote PCa progression. We and others have recently reported FOXA1 down-regulation in metastatic castration resistant prostate cancer (CRPC) and loss in neuroendocrine PCa (NEPC). FOXA1 is found accountable for PCa de-differentiation and tumor metastasis. However, how FOXA1 expression levels are regulated during PCa progression remains largely known. TRIM25 is a member of tripartite motif (TRIM)-containing proteins known as E3 ubiquitin ligase via RING-finger domain. In some cancers, TRIM25 overexpression has been shown to activate TGF-beta signalling, increases cancer cell invasion, and promotes tumor metastasis. And yet, there are very limited studies of TRIM25 in PCa and its key function and downstream mediators are yet to be characterized. Our preliminary data revealed that FOXA1 is a potential substrate of TRIM25 in PCa. TRIM25 is up-regulated in metastatic PCa. Being concordant with TRIM25, FOXA1 loss also induces TGF-beta signalling and PCa metastasis and anti-androgen resistance. Thus, our central hypothesis is that TRIM25 promotes PCa metastasis and progression through ubiquitination and degradation of FOXA1. To test this hypothesis, we propose two Specific Aims. Aim 1. Characterize how TRIM25 regulates FOXA1 protein stability and correlate TRIM25 expression in human PCa tissues with FOXA1 levels and clinical outcomes. Aim 2. Investigate the roles of TRIM25-FOXA1 in regulating PCa metastasis and progression. Innovation: This will be a first study to perform comprehensive analysis of TRIM25 as a transcriptional and translational regulator in PCa. FOXA1 as a substrate of TRIM25 is entirely novel. In addition, it is novel to examine the mechanisms responsible for FOXA1 post-translational modifications and protein stabilities during PCa progression. Impact: Understanding the molecular mechanisms responsible for FOXA1 loss may provide novel therapeutic approaches to prevent or revert PCa de-differentiation. For example, blockade of TRIM25 ligase activity may be useful in restoring FOXA1 expression and re-sensitizing tumors to anti-androgen treatment. On the other hand, TRIM25 up-regulation may be a useful biomarker for PCa sensitivity to TGF-beta pathway inhibitors. This project thus addresses the Overarching Challenge to “Define the biology of lethal PCa to reduce death” and “Develop treatments that improve outcomes for men with lethal PCa”.