Noncanonical activities of SETD7 in preventing prostate cancer progression andtherapy resistance - PROJECT SUMMARY Background: Epigenetic dysregulation involving lysine methyltransferases and demethylases play a critical role in the progression of prostate cancer (PCa) and its resistance to androgen deprivation therapies (ADT) and androgen receptor signaling inhibition therapies (ARSi). Our prior research has demonstrated that LSD1 promotes oncogenic development by demethylating lysine 270 on FOXA1, a key pioneer factor in driving castration-resistant prostate cancer (CRPC) progression, thereby enhancing its chromatin binding and enhancer accessibility. In our recent report, we further revealed that SETD7, originally known as an activator of gene transcription by methylating histone 3 lysine 4, specifically targets FOXA1-K270 for methylation, acting as a negative regulator of the LSD1-FOXA1 epigenetic axis in PCa cells. Subsequently, we identified a tumor- suppressive function of SETD7, noting that CRPC tumors with reduced SETD7 expression correlate strongly with poor clinical outcomes. Additionally, we observed that SETD7 deficeincy leads to a redistribution of FOXA1 chromatin binding, facilitating the progression of prostate tumors and the resistance to ARSi. Hypothesis/Objective: (1) We hypothesize that SETD7 is crucial in preventing tumor progression by negatively controlling LSD1-mediated oncogenic activities in PCa cells. Thus, a reduction in SETD7 levels and activities may allow PCa cells to become resistant to ARSi by adapting to LSD1-FOXA1-induced transcriptional reprogramming. (2) We further hypothesize that the SETD7 deficiency in CRPC generates vulnerabilities that can be intervened with epigenetic treatments designed to target LSD1-FOXA1-mediated epigenetic reprogramming. Specific Aims: Aim 1 is to assess SETD7 protein expression and its correlation with SETD7 targets, LSD1, AR, and other key epigentic regulators in CRPC specimens, and to investigate AR regulation of SETD7 transcription. Aim 2 is to delineate the mechanisms underlying SETD7's tumor suppressive activity, focusing on its role in restricting FOXA1 chromatin binding and preventing reprogramming of the Super-Enhancer-driven transcription network. Aim 3 is to target vulnerabilities induced by SETD7 deficiency and evaluate the effectiveness of these treatment strategies in SETD7-deficient CRPC using cell line and patient-derived xenografts (PDXs). Impact: Should this study succeed, its immediate outcome will be to elucidate the mechanisms through which SETD7 exerts its noncanonical tumor-suppressive and transcription-repressive roles in PCa progression and treatment resistance, as well as to pinpoint actionable targets for the development of therapies aimed at combatting the aggressive subtype of CRPC characterized by SETD7 deficiency. Over the long term, the goal is to translate these therapeutic strategies targeting SETD7-loss vulnerabilities into clinical trials for a well- defined subset of CRPC patients, thereby enhancing patient outcomes.
