TRIM28 fuels prostate cancer growth through SETDB1-mediated epigenetic silencing of androgen metabolic genes UGT2B15 and UGT2B17 (Project #3)

Grants and Contracts Details


Prostate cancer (PCa) is the second-leading cause of cancer-related death in men. The mainstay treatment for metastatic PCa is androgen deprivation therapy (ADT). However, the disease will inevitably return in an incurable form termed castration-resistant prostate cancer (CRPC). Importantly, aberrant androgen receptor (AR) activation in the milieu of low androgen is the main driver of CRPC. Molecular characterization of CRPC paves the way for discovery of novel therapeutic targets, and my previous studies showed that TRIM28 is aberrantly upregulated in advanced PCa. High TRIM28 levels are associated with worse clinical outcomes, which suggests that TRIM28 could serve as a promising target for PCa therapy. It is known that TRIM28 in a complex with trimethyl-histone H3 lysine 9 (H3K9me3)-specific methyltransferase (SETDB1) possesses transcriptional co-repressor activity but its genomic targets remain largely unexplored in PCa. Moreover, the TRIM28 downstream oncogenic pathway has not been comprehensively investigated in PCa. By molecular gene signature analysis, I found that the steroid hormone metabolic pathway is regulated by TRIM28. In particular, I found that the androgen eliminating enzymes UGT2B15 and UGT2B17 are the key TRIM28-repressed genes. It is known that genomic targeting of the TRIM28 complex is facilitated by transcription factors that bind to specific DNA recognition motifs. My data revealed that TRIM28 interacts with AR. In addition, my preliminary results indicated there is co-occupancy of TRIM28, AR and H3K9me3 deposition at UGT2B15 and UGT2B17 gene loci. Based on these findings, I hypothesize that TRIM28 acts together with AR to epigenetically silence the expression of androgen metabolic enzymes through SETDB1-mediated H3K9me3. I propose to test this hypothesis in Aim1. UGT2B15 and UGT2B17 are known to inactivate androgen through glucuronidation using UDPGlucA as the sugar-donor. Given that the overexpression of UGT2B15 and UGT2B17 correlate to more UDP-GlucA consumption, I hypothesize that levels of UDP-GlucA will decrease in TRIM28 knockdown cells or with treatment of the SETDB1 inhibitor, Mit, in CRPC cells. I propose to test this hypothesis in Aim2. The results from this proposal will not only reveal a novel epigenetic mechanism for regulating androgen glucuronidation, but also have significant implications for the development of SETDB1-targeted therapy for CRPC treatment.
Effective start/end date8/13/2112/31/21


  • National Institute of General Medical Sciences


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