Role of E3 Ubiquitin Ligase TRIM25 in Prostate Cancer
Abstract
Scientific Rationale, Objectives, and Aims: Prostate cancer (PCa) is the second most commonly diagnosed cancer in American men. While localized disease is largely curable, metastatic PCa remains lethal. The mainstay treatment for metastatic PCa is androgen-deprivation therapy combined with new generation androgen receptor (AR) pathway inhibitors such as abiraterone, enzalutamide, and apalutamide. Yet patients often develop resistance within several months to years of treatment, reaching a stage termed metastatic castration-resistant prostate cancer (mCRPC). Genes and molecular pathways that drive metastasis, the lethal conversion of the disease, are thus important targets for therapeutic intervention. Tripartite motif-containing protein 25 (TRIM25) was recently shown to be a key determinant of breast cancer metastasis. However, TRIM25 has not been carefully studied in PCa. Our preliminary analyses of public datasets revealed that TRIM25 is also strongly up-regulated in mCRPC compared to primary PCa. Further, an elevated level of TRIM25 is significantly associated with shorter biochemical-free survival, a measure of metastatic progression by definition. To gain some insights into the molecular functions of TRIM25 in PCa, we examined the genes that are induced by TRIM25 overexpression. We observed strong enrichments in epithelial-to-mesenchymal transition (EMT) and Transforming Growth Factor (TGF)-beta signaling, both of which are key drivers for cancer metastasis. Next, we sought to decipher the molecular mechanisms by which TRIM25 regulate these metastatic pathways. As TRIM25 is an E3 ubiquitin ligase, which binds to target substrates to mediate protein degradation, we examined TRIM25-interacting proteins and found that TRIM25 directly interacts with FOXA1 (forkhead box protein A1). FOXA1 is a transcription factor that is essential for maintenance of the epithelial phenotype of prostate cells. Previous studies have shown that FOXA1 loss results in EMT, increased cell motility, and tumor metastasis. This oncogenic role is mediated by TGF-beta activation and thus can be blocked by the clinically available TGF-beta pathway inhibitor LY2157299. Taken together, we hypothesize that TRIM25 promotes PCa metastasis through, at least in part, degrading FOXA1 protein and activating TGF-beta signaling, and that TGF-beta pathway inhibitors will be effective in abolishing TRIM25-driven PCa metastasis. To test our hypotheses, in Aim 1, we will characterize the mechanistic details by which TRIM25 binds to FOXA1 to mediate its degradation and demonstrate that TRIM25 robustly decreases FOXA1 protein levels to activate TGF-beta signaling using multiple PCa cell line models. We will also examine their expression in human PCa specimens to confirm regulation and evaluate the potential of TRIM25 to predict PCa metastasis. Next, to demonstrate the oncogenic roles of TRIM25-FOXA1 axis in driving PCa cell motility and tumor metastasis, in Aim 2, we will perform various functional assays in vitro and xenograft tumor studies in mice using PCa cells with TRIM25 overexpression or knockdown followed by appropriate FOXA1 rescue. Further, using xenografts and PDX models, we will test whether TGF-beta pathway inhibitor LY2157299 abolishes TRIM25-driven tumor metastasis and whether it provides additional therapeutic benefits to AR pathway inhibitors, such as enzalutamide, that are used in the standard of care for metastatic PCa patients. Ultimate Applicability of the Research: This study addresses the Overarching Challenges of “Define the biology of lethal PCa to reduce death” and “Develop treatments that improve outcomes for men with lethal PCa.” It will help metastatic PCa patients through identifying TRIM25 as a major driver of tumor metastasis that can be targeted by TGF-beta pathway inhibitors. LY2157299 is currently in a Phase 2 clinical trial (NCT02452008) and being tested in combination with enzalutamide for mCRPC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110548
Entities
People
- Jindan Yu
Organizations
- Northwestern University
- United States Army