The Role of SETDB1 in Prostate Cancer

ABSTRACT Androgen receptor (AR) signaling is a driving force behind early-stage to castration-resistant prostate cancer (CRPC). While androgen signaling inhibitors (ASIs) like enzalutamide (Enz) serve as standard treatments for CRPC, the development of resistance remains inevitable. The long-term goals of this study are to identify new targets and therapies for ARSI-resistant CRPC. Emerging evidence indicates that Epithelial-Mesenchymal Transition (EMT) is deregulated during PCa progression, contributing to PCa metastasis and therapeutic resistance. Therefore, addressing the knowledge gap on how EMT is regulated may identify novel actionable target for the development of novel therapeutics. Our research uncovers SETDB-RhoB pathway regulate EMT in PCa. Preliminary results reveal that that the frequent gain of SETDB1 in 15% of metastatic CRPC patients epigenetically downregulate RhoB expression, resulting in deregulated EMT, metastasis and resistance to ASI-therapy. By utilizing SETDB1-antisense oligo (ASO) and inhibitor of RhoB-specific ubiquitination, we have successfully reinstated EMT suppression and impeded the metastasis of Enz-resistant PCa tumors. In light of these compelling findings, we propose three aims to validate the central hypothesis that SETDB1 promotes PCa metastasis via RhoB-loss induced EMT-program. SETDB1 inhibition or RhoB restoration by clinically- available NEDD8-activating enzyme inhibitor MLN4924 mitigate PCa metastasis and therapeutic resistance. The study is structured around three specific aims: (1) Investigate whether catalytic activity of SETDB1 regulates RhoB and promotes PCa metastasis. (2) Elucidate the mechanism by which RhoB suppress EMT and PCa metastasis. (3) Evaluate whether SETDB1 inhibition and RhoB restoration is a novel approach to treat ASI-resistant CRPC. To achieve these aims, we are employing state-of-the-art technologies such as CUT&RUN, ATAC-seq, and RNA-seq, utilizing orthoptic intraprostatic injection model and human PCa samples. If the results of the proposed research are positive, it has the potential to support SETDB-ASO and MLN4924 in combination with Enz as a novel approach to treat ASI- resistant CRPC.