Minimal-length CAG repeats in <i>AR</i> define a hyperactive AR-LSD1 axis driving metabolic reprogramming in prostate cancer.

Abstract

The polymorphic CAG trinucleotide repeat in the androgen receptor (<i>AR</i>) gene encodes a variable-length N-terminal polyglutamine (polyQ) tract that modulates AR transcriptional activity, with shorter tracts generally enhancing AR activity. While the majority of men harbor CAG repeats longer than 17, a small subset carry minimal-length CAG repeats (≤17) in <i>AR</i>. These alleles are primarily found in men of African ancestry, accounting for over 10% of the population, and may significantly contribute to the increased prostate cancer (PCa) risk and worse clinical outcomes observed in this population. 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 <i>AR</i> with a minimal length of CAG repeats that encode an ultrashort polyQ tract and found that this AR variant exhibits attenuated response to AR-targeted therapies with markedly enhanced protein stability, expanded chromatin binding, and a reprogrammed transcriptional profile. The ultrashort polyQ AR also reshapes global FOXA1 occupancy and upregulates metabolic gene networks, leading to enhanced glycolysis and reduced mitochondria respiration. Mechanistically, we identify a strengthened AR-LSD1 interaction and show that LSD1 inhibition suppresses the expanded AR chromatin binding, impairs the glycolytic reprogramming, and reduces tumor growth. Together, these findings define a hyperactive AR-LSD1 chromatin axis driven by minimal-length CAG repeats in <i>AR</i> and reveal a mechanistic link between inherited <i>AR</i> polymorphism, AR-mediated epigenetic-metabolic remodeling, and population-associated disparities in prostate cancer biology.