Abstract 1464: Zaniya Mark

Abstract Prostate cancer (PCa) is one of the most common types of cancers diagnosed in American men. Moreover, PCa malignancy disproportionally strikes more on African American (AA) men than any other ethnic groups including Caucasian American (CA) men. Forkhead Box A1 (FOXA1) is frequently mutated in hormone receptor-driven cancers including PCa. FOXA1 mutation rates in AA PCa specimens are 3-fold higher than that in CA PCa. By annotating the FOXA1 mutation landscape two hotspots were defined in AA PCa patients located in the forkhead domain: D226N and R219C. FOXA1 expression and functions are regulated by lysine [K]-specific demethylase 5B (KDM5B). KDM5B contributes to the activation of signaling pathways that promote cancer progression. Here in this project, we will focus on the mechanistic role of FOXA1 dysregulation and its interaction with KDM5B and AR on PCa progression in AA vs CA PCa cells. Therefore, we hypothesize that the dysregulation of FOXA1 plays an essential role in the progression of PCa by altering chromatin remodeling and AR interaction, and FOXA1 mutation promotes more aggressive malignancies in AA PCa cells. In order to investigate the biological function and regulation of FOXA1 in PCa cells we first need to knockout (KO) the endogenous expression using CRISPR technology and then knockin (KI) the unique mutants R219C and D226N. These in vitro studies of FOXA1 mutations found in AA PCa will be critical to determine the biological functions of these mutants for PCa progression. The findings from this study will provide valuable insights into the contributions of the FOXA1 regulation and will add to our knowledge base for the potential development of a novel therapeutic strategy to reduce PCa disparities between AA and CA populations. This project was supported, in part, by MVTCP Cancer Partnership Grant U54 CA163069. Citation Format: Zaniya A. Mark, Guoliang Li, Robert Matusik, Zhenbang Chen. Zaniya Mark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1464.