The androgen receptor (AR) is a transcription factor whose overactivation is a primary driver of prostate cancer. Although AR interactions with several long non-coding RNAs (lncRNAs) have been implicated in castration-resistant prostate cancer, their underlying molecular mechanisms and functional consequences remain poorly understood. Here, we identify the N-terminal 37 residues of the intrinsically disordered AR N-terminal domain as the primary RNA-binding region that mediates selective interactions with the lncRNAs HOTAIR and SLNCR1. Residue-level mapping and mutational analysis define Y11, R13, and Q24 as key determinants of RNA recognition. This RNA-binding region partially overlaps with the F23QNLF27 motif, previously shown to mediate N/C interdomain communication with the ligand-binding domain through folding upon binding. We observe a partner-dependent binding mode in which this motif remains dynamically disordered upon RNA binding. LncRNA binding promotes phase separation of the N-terminal domain, indicating that lncRNAs upregulated in late-stage prostate cancer may lower the threshold for AR condensate formation and contribute to ligand-independent AR signaling. LncRNAs modulate communication between the N-terminal and ligand-binding domains within condensates, suggesting that lncRNA binding may tune hormone-dependent full-length AR signaling. These findings provide a mechanistic framework for AR-lncRNA regulation, laying the groundwork for future therapeutic strategies against advanced prostate cancer.
Farahi, N., Balatti, G. E., Volkov, A. N., Pancsa, R., Tompa, P., Loris, R.
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