Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. Glucocorticoids (GCs) are administered to PCa patients and have been implicated in therapy resistance. This may be critical to AA men with PCa since they have elevated endogenous GCs levels compared to Caucasian American (CA) men. GCs bind to the glucocorticoid receptor (GR) to exert their actions. The mechanisms of GR-mediated chemoresistance, and its possible contribution to PCa mortality disparities are unknown. We demonstrated that GCs upregulate the chemoresistance-associated protein and transcription co-activator LEDGF/p75 in PCa cells and identified consensus GR binding sites in the promoter region of this protein. Given that both GR and LEDGF/p75 are components of the RNA polymerase II transcription complex, we hypothesized that GR transcriptionally upregulates LEDGF/p75 and then interacts with it to enhance taxane resistance in PCa cells. Pharmacological and genetic inhibition of GR in a panel of docetaxel (DTX)-sensitive and -resistant PCa cells decreased the expression of LEDGF/p75, confirming its status as a candidate GR target gene. However, silencing of LEDGF/p75 had no effects on GR expression. Immunoprecipitation studies revealed that GR and LEDGF/p75 interact in DTX-sensitive and -resistant PCa cells. This interaction was confirmed by confocal microscopy. Immunohistochemical analysis of GR and LEDGF/p75 expression in normal and tumor prostate tissues was performed and the results are currently being analyzed. Our studies use a mechanistic approach to evaluate the potential contribution of the GR-LEDGF/p75 axis to PCa chemoresistance. Evaluating the co-expression of these proteins in racially diverse PCa tissues may also reveal race-related differential expression, providing insights into the potential contribution of this axis to PCa chemoresistance and mortality disparities.

Citation Format: Evelyn S Sanchez-Hernandez, Greisha L. Ortiz-Hernandez, Pedro T. Ochoa, Christian R Gomez, Carlos A Casiano. Contribution of the GR-LEDGF/p75 axis to prostate cancer chemoresistance [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-145.