Abstract 3089: Silencing the stress oncoprotein LEDGF/p75 reveals potentially novel roles in lymphocyte function and inflammation

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortality for men in the U.S. Although the five-year survival rate for localized PCa is nearly 100%, once the disease progresses to later stages patients ultimately develop therapy resistance and the survival rate drops to roughly 30%. Understanding the mechanisms underlying PCa therapy resistance is crucial for developing new treatment options. Our recent studies have implicated the glucocorticoid receptor (GR)-lens epithelium derived growth factor p75 (LEDGF/p75) axis in PCa resistance to docetaxel (DTX). We demonstrated that GR upregulates and interacts with LEDGF/p75 in DTX-resistant PCa cells and that both proteins contribute to chemoresistance by regulating gene pathways associated with stress survival. LEDGF/p75 is a cellular survival protein that is upregulated in cancer cells exposed to environmental stressors, including cytotoxic drugs, and plays an important role in cellular protection against stress-induced cell death. This study was designed to gain mechanistic insights into the biological functions of LEDGF/p75 in DTX-resistant PCa cells. We silenced LEDGF/p75 expression in chemoresistant PCa cells via RNA interference, followed by RNA-sequencing (RNA-seq) analysis. Robust LEDGF/p75 silencing, confirmed by Western blotting, led to the identification of 970 differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) revealed a role for this protein in the regulation of gene pathways that are normally associated with B cell and T cell responses and inflammatory responses. For instance, LEDGF/p75 knockdown led to upregulation of the inflammatory cytokines IL7R and IL18, as well as several MHC class I genes, implicating this protein in suppressing inflammatory responses. Using publicly available RNA-seq data for various immune cells we also found evidence for LEDGF/p75 promoting CD4 and CD8 T cell activation. In addition, using public scRNA-seq data, we observed that LEDGF/p75 is found in T cell clusters for various cancer types, further suggesting immune functions in a broad array of tissues. Thus, understanding the novel roles of LEDGF/p75 in immunity may provide new insights into its biological and tumorigenic functions, and its potential role in modulating responses to immunotherapy. Citation Format: Pedro Toscano Ochoa,Evelyn S. Sanchez-Hernandez,Kai Wen Cheng,Zhong Chen,Isaac Kremsky,Charles Wang,Carlos A. Casiano. Silencing the stress oncoprotein LEDGF/p75 reveals potentially novel roles in lymphocyte function and inflammation [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 3089.