Minimal-length CAG repeats in AR define a hyperactive AR-LSD1 axis driving metabolic reprogramming in prostate cancer [RNA-Seq]

While the majority of men harbor CAG repeats longer than 17, a small subset carry minimal-length CAG repeats (≤17) in AR. These alleles are primarily found in men of African ancestry (AA), accounting for over 10% of the population, and may significantly contribute to the increased prostate cancer (PCa) risk and worse clinical outcomes observed in AA men.

However, how this distinct pattern of polymorphism influences AR-chromatin interaction, metabolic reprogramming, and therapeutic response remains unclear. Here, we established isogenic PCa cell lines harboring AR with a minimal length of CAG repeats that encode an ultrashort polyQ track and found that this AR variant exhibits resistance to AR-targeted therapy with markedly enhanced protein stability, expanded chromatin binding, and a reprogrammed transcriptional profile.