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

• 成果类型: Article
• 署名作者: Zhang, Songqi; Li, Muqing; Liu, Mingyu; Patten, Nolan D.; Labaf, Maryam; Jeong, Jaeweon; Sun, HyeonYeong; Lourie, Jared; Zou, Kai; Patalano, Susan; Mulhearn, Michaela J.; Macoska, Jill A.; Gao, Shuai; Andreotti, Roberta; Pennuto, Maria; Han, Dong; Balk, Steven P.; Cai, Changmeng
• 署名单位: University of Massachusetts System; University of Massachusetts Boston; University of Massachusetts System; University of Massachusetts Boston; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Massachusetts System; University of Massachusetts Boston; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; University of Massachusetts System; University of Massachusetts Boston; New York Medical College; University of Padua; Veneto Institute Molecular Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2534152123
• 发表日期: 2026-09-15
• 页码: e2534152123
• 关键词: prostate cancer; ANDROGEN RECEPTOR; polyglutamine repeats; cancer racial disparity; lsd1; ANDROGEN RECEPTOR GENE; AFRICAN-AMERICAN MEN; resistance; phosphorylation; expression

摘要

The polymorphic CAG trinucleotide repeat in the androgen receptor (AR) 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 AR. 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 AR 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 AR and reveal a mechanistic link between inherited AR polymorphism, AR-mediated epigenetic-metabolic remodeling, and population-associated disparities in prostate cancer biology.