Abstract 6728: Investigating the effect of male-specific lysine demethylase 5D alteration on oncogenic behavior in human prostate cancer cells

Abstract Prostate cancer (PC) is the most common urological malignancy, with approximately 11% of men being diagnosed with it during his lifetime and is the second leading cause of cancer-related fatalities in males. One of the challenges in treating advanced, symptomatic prostate cancer is the limited effectiveness of the standard care, androgen deprivation therapy (ADT), in late-stage disease. While somatic Y chromosome (ChrY) loss in men has been associated with an increased risk of several diseases, including prostate cancer, the role of ChrY genes in prostate cancer progression and chemotherapy resistance remains understudied. Based on significant epidemiological and genomic data generated by multiple teams, including ours, this present study critically examines the contributions of the loss of the chromosome Y gene lysine demethylase 5D (KDM5D) to chromosome Y-null prostate cancer progression and resistance to ADT. In our approach to investigating this phenomenon we have employed a number of advanced techniques which interrogate the epigenomic, transcriptomic, proteomic, and behavioral landscape of defined prostate cancer lines with genetically altered levels of KDM5D RNA and protein. Herein, lentiviral transduction was employed to perform CRISPR-mediated KDM5D knockout with three novel gRNAs in each castration sensitive and insensitive prostate lines (LNCaP and 22RV1, respectively). Single cell-derived clones from each of the six lines infected with this CRISPR knockout virus have been isolated and individually expanded to measure the impacts of KDM5D knockout accurately with respect to target expression and Cas9 copy number; to date, several subclones have shown satisfactory reductions in KDM5D expression and are now being subjected to functional and behavioral assays pursuant to analyzing its malignant characteristics, alterations in gene expression, and changes in androgen deprivation and/or chemotherapeutic agent sensitivity. Moreover, we have employed KDM5D addback to create an overexpression model in ChrY-null PC3M cells. Thus far, the loss of KDM5D has been shown to contribute to increased oncogenic behavior in prostate cancer cells and may be associated with a poor patient prognosis. Our preliminary data provide mechanistic evidence that KDM5D expression influences several DNA damage repair pathways in prostate cancer cells .Ultimately, the goal of our group is to identify alternative therapeutic targets, chemotherapeutic agents, and ultimately characteristics of clinically consequential prognostic value in KDM5D/ChrY-null prostate cancers where currently no treatments are available. Citation Format: Sarah Ann S. King, Nabila Zaman, Prathiksha Prabhakaraalva, Goutam Chakraborty. Investigating the effect of male-specific lysine demethylase 5D alteration on oncogenic behavior in human prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6728.