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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>\n                    The polymorphic CAG trinucleotide repeat in the androgen receptor (\n                    <jats:italic toggle=\"yes\">AR<\/jats:italic>\n                    ) 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 (\u226417) in\n                    <jats:italic toggle=\"yes\">AR<\/jats:italic>\n                    . 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\u2013chromatin interaction, metabolic reprogramming, and therapeutic response remains unclear. Here, we established isogenic PCa cell lines harboring\n                    <jats:italic toggle=\"yes\">AR<\/jats:italic>\n                    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\u2013LSD1 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\u2013LSD1 chromatin axis driven by minimal-length CAG repeats in\n                    <jats:italic toggle=\"yes\">AR<\/jats:italic>\n                    and reveal a mechanistic link between inherited\n                    <jats:italic toggle=\"yes\">AR<\/jats:italic>\n                    polymorphism, AR-mediated epigenetic-metabolic remodeling, and population-associated disparities in prostate cancer biology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2534152123","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:26:36Z","timestamp":1788971196000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Minimal-length CAG repeats in\n                    <i>AR<\/i>\n                    define a hyperactive AR\u2013LSD1 axis driving metabolic reprogramming in prostate cancer"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8719-376X","authenticated-orcid":false,"given":"Songqi","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Personalized Cancer Therapy, University of Massachusetts Boston","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Massachusetts Boston","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muqing","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Personalized Cancer Therapy, University of Massachusetts Boston","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Massachusetts Boston","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Urology, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Personalized Cancer Therapy, University of Massachusetts Boston","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04ydmy275","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, University of Massachusetts Boston","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1817-236X","authenticated-orcid":false,"given":"Nolan 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repeats in the androgen receptor gene: Molecular markers of prostate cancer risk","volume":"57","author":"Stanford J. L.","year":"1997","unstructured":"J. L. Stanford , Polymorphic repeats in the androgen receptor gene: Molecular markers of prostate cancer risk. Cancer Res. 57, 1194\u20131198 (1997).","journal-title":"Cancer Res."},{"key":"e_1_3_4_17_2","first-page":"255","article-title":"The androgen receptor CAG repeat and prostate cancer risk","volume":"81","author":"Clark P. E.","year":"2003","unstructured":"P. E. Clark, R. A. Irvine, G. A. Coetzee, The androgen receptor CAG repeat and prostate cancer risk. Methods Mol. Med. 81, 255\u2013266 (2003).","journal-title":"Methods Mol. 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S.","year":"1996","unstructured":"C. S. Choong, J. A. Kemppainen, Z. X. Zhou, E. M. Wilson, Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol. Endocrinol. 10, 1527\u20131535 (1996).","journal-title":"Mol. Endocrinol."},{"key":"e_1_3_4_57_2","unstructured":"S. Zhang M. Li M. Liu C. Cai Data from \u201cMinimal-length CAG repeats in AR define a hyperactive AR-LSD1 axis driving metabolic reprogramming in prostate cancer [ChIP-Seq].\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE310685. Deposited 20 November 2025."},{"key":"e_1_3_4_58_2","unstructured":"S. Zhang M. Li M. Liu C. Cai Data from \u201cMinimal-length CAG repeats in AR define a hyperactive AR-LSD1 axis driving metabolic reprogramming in prostate cancer [RNA-Seq].\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE310689. Deposited 20 November 2025."},{"key":"e_1_3_4_59_2","unstructured":"S. Gao D. Han S. Chen H.H. He C. Cai Data from \u201cAR ChIP-seq with DHT induction and GSK treatment.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE114266. Deposited 9 May 2018."},{"key":"e_1_3_4_60_2","unstructured":"H. H. He C. Cai S.P. Balk M. Brown Data from \u201cLysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE52201. Deposited 7 November 2013."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2534152123","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2534152123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:26:42Z","timestamp":1788971202000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2534152123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":60,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2026,9,15]]}},"alternative-id":["10.1073\/pnas.2534152123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2534152123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"2025-11-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2534152123"}}