8805 Nucleostemin is a novel bifunctional transcriptional coregulator of theandrogenreceptorin prostate cancer cells

Abstract Disclosure: E. Cheung: None. C. Zhang: None. Androgen receptor (AR) is a master transcriptional regulator in prostate cancer, interacting with and recruiting distinct sets of coregulator proteins to mediate the expression of direct target genes. What are the coregulators of AR and how they function in AR transcriptional activity and prostate cancer biology are still unclear. Using chromatin-immunoprecipitation coupled with mass spectrometry, we identified a set of AR interacting proteins that are present in multiple prostate cancer cell lines. We provide biochemical, cell-based, and genomic evidence to show that Nucleostemin, also known as Guanine nucleotide-binding protein-like 3, is a novel AR coregulator. Specifically, we demonstrate Nucleostemin has dual coregulator activities, functioning as both a coactivator and a corepressor of AR-dependent transcription to regulate the expression of genes that are involved for prostate cancer progression and immune response. From cellular and animal studies, we found that inhibiting Nucleostemin sensitizes prostate cancer cells to Enzalutamide. Clinical analyses of Nucleostemin from prostate cancer patient cohorts revealed that it is expressed significantly higher in cancer than normal in tissues. Finally, we found Nucleostemin expression is an excellent predictor of disease-free survival. In conclusion, our work suggests that Nucleostemin is a novel AR coregulator and is a promising diagnostic and therapeutic target for prostate cancer treatment. Presentation: 6/2/2024