Abstract Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well recognized, with men of African ancestry (AA) exhibiting more aggressive disease. One germline genetic factor contributing to this disparity is the polymorphic CAG trinucleotide repeat in the first exon of the androgen receptor (AR) gene, which encodes a variable-length polyglutamine (polyQ) tract within the AR N-terminal domain. Shorter polyQ tracts, commonly found in the AA population, are reported to associate with enhanced AR transcriptional activity and increased PCa risk. Notably, minimal-length CAG repeats, defined as ≤17, are present in ∼10% AA men but are rare among men of European ancestry (EA). These encode ultrashort polyQ tracks, however, how such variations alter AR chromatin function, its transcriptional output, metabolic reprogramming, and therapeutic response remains unclear. Methods: We performed CRISPR/Cas9 editing to generate isogenic LNCaP-derived prostate cancer cell lines harboring minimal-length CAG repeats (10Q) AR alleles. Integrated analyses combining RNA-seq, ChIP-seq, and functional studies in vitro and in vivo were conducted to define the transcriptional, epigenetic, and metabolic consequences of ultrashort polyQ AR. Results: The 10Q AR variant exhibited markedly reduced proteasomal degradation, leading to enhanced AR protein stability and resistance to AR antagonist-induced protein degradation. Genome-wide analyses revealed markedly expanded AR chromatin binding and redistribution of the pioneer transcription factor FOXA1, accompanied by transcriptional activation of lipid biosynthesis and glycolysis genes. Mechanistically, the ultrashort polyQ tracks strengthened AR interaction with the epigenetic coactivator LSD1, enhancing its coactivator activity. Pharmaceutical inhibition of LSD1 with iadademstat (ORY-1001) suppressed AR-mediated metabolic reprogramming and significantly reduced tumor growth in 10Q xenograft models. Conclusion: Minimal-length CAG repeats in AR establish a hyperactive AR-LSD1 chromatin axis that drives transcriptional and metabolic reprogramming, leading to prostate cancer progression. These findings link inherited germline AR polymorphism to epigenetic-metabolic remodeling and identify LSD1 inhibition as a promising therapeutic strategy for aggressive and racially disparate PCa subtypes harboring minimal-length CAG repeats. Citation Format: Songqi Zhang, Muqing Li, Mingyu Liu, Nolan D. Patten, Maryam Labaf, Jaeweon Jeong, HyeonYeong Sun, Jared G. Lourie, Kai Zou, Susan Patalano, Jill A. Macoska, Shuai Gao, Dong Han, Maria Pennuto, Steven P. Balk, Changmeng Cai. Minimal-length CAG repeats in AR define a hyperactive AR-LSD1 axis driving metabolic reprogramming in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2287.
Zhang et al. (Fri,) studied this question.