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Pinette, Nicholas Conrad

University of British Columbia

Prostate cancer (PCa) is the most commonly diagnosed cancer among Canadians assigned males at birth. The disease is driven primarily by the androgen receptor (AR), a ligand-activated transcription factor. We recently showed that the full-length AR forms nuclear condensates upon androgen stimulation in both PCa models and in vitro. These condensates colocalize with components of the transcriptional machinery and potentially control gene transcription. However, the mechanisms underlying condensate formation, the specific sequences or regions driving this process, and whether they activate distinct cancer-associated pathways remain unknown. This work aimed to identify AR mutants that specifically disrupt condensate formation without impairing expression levels or nuclear translocation. To this end, the study first examined how known AR mutations influence the receptor's ability to form condensates. Subsequently, we employed bioinformatics tools to predict AR residues and regions with high propensities to control condensate formation, which were then experimentally evaluated for their effects using cell-based assays. The E898A mutant in the Ligand-Binding Domain Activation Function 2 (LBD-AF2) pocket had the greatest impact on condensate formation, highlighting the essential role of coactivator recruitment through this pocket in regulating condensate dynamics of the full-length receptor. We also predicted and experimentally assessed two-point mutations, P133I and P135I, located within Tau-1 of the AR, and found that they reduced AR nuclear condensates by at least 40% compared to the wild-type. We also identified the region spanning residues 412-497 as important for condensate formation. These results suggest that interfering with residues involved in cofactor recruitment could inhibit oncogenic condensate formation in PCa.

Text; Still Image

2025-02-13

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90362

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/