No abstract

In The United States of America 1 in 8 men will develop prostate cancer (PCa) in their lifetime. The assembly of phase-separated condensates containing players of the transcriptional machinery such as transcription factors, coactivators (e.g. MED1), and RNA polymerase II enhances the transcription of key oncogenes in various cancer including PCa. Many proteins undergoing phase-separation possess intrinsically disordered regions (IDR) that mediate multivalent intra- and inter-molecular interactions, essential for condensate formation. We recently demonstrated that full-length AR, the main oncogenic driver in PCa, is more prone to form nuclear transcriptional condensates upon androgen stimulation in PCa models than in benign epithelial prostate models. In this study, we investigated the effects of mutating or truncating key residues or regions involved in AR transcriptional activity on its ability to form nuclear condensates in LNCaP cells as visualized by confocal microscopy. We also used various bioinformatics tools to predict additional AR residues and sequences with high propensity for phase-separation. We thus made various truncations and mutations and evaluated their ability to form condensates in LNCaP cells. We also tested the effect MED1 phosphorylation and treatment with various inhibitors targeting different domains of the AR on the ability of full-length protein to form droplets in vitro. We hope by better understanding what drive AR condensates formation in PCa, to elucidate this new mechanism of transcriptional regulation and to identify new therapeutic avenues for patients with advanced forms of the disease. Citation Format: Nicholas C. Pinette, Shabnam Massah, Sofia Kochkina, Fan Zhang, Maitree Biswas, Joseph Lee, Jörg Gsponer, Nada Lallous. Characterization of androgen receptor properties and interactome in mediating transcriptional condensates in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5292.