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Adv."],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:p>\n                    Cyclin-dependent kinase 4\/6 inhibitors (CDK4\/6i) are standard therapies for estrogen receptor\u2013positive breast cancer, but their efficacy is limited by drug resistance. While dysregulation of alternative splicing has been implicated in cancer progression, the underlying mechanisms remain unclear. Here, we uncover a splicing-mediated mechanism whereby exon 2 inclusion in\n                    <jats:italic toggle=\"yes\">SUV39H2<\/jats:italic>\n                    drives its overexpression in CDK4\/6i-resistant breast cancer cells. Clinically, elevated exon 2 inclusion in\n                    <jats:italic toggle=\"yes\">SUV39H2<\/jats:italic>\n                    correlates with poor prognosis in patients with breast cancer. Targeting\n                    <jats:italic toggle=\"yes\">SUV39H2<\/jats:italic>\n                    with gapmer antisense oligonucleotides or a methyltransferase inhibitor overcomes CDK4\/6i resistance and reinstates therapy-induced senescence in breast cancer cells by reducing SUV39H2 expression or activity. Mechanistically, targeting\n                    <jats:italic toggle=\"yes\">SUV39H2<\/jats:italic>\n                    promotes transcriptional activation of senescence-associated secretory phenotype genes, including\n                    <jats:italic toggle=\"yes\">p21<\/jats:italic>\n                    , through H3K9me3 removal at enhancer regions and subsequent chromatin opening at promoters. Our work unveils a splicing-mediated resistance mechanism and presents a potential synergistic drug target for CDK4\/6i therapy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea2001","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:06:59Z","timestamp":1791569219000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Targeting SUV39H2 exon skipping reverses resistance to CDK4\/6 inhibitors via transcriptional activation of p21"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9926-852X","authenticated-orcid":true,"given":"Shiyi","family":"Yu","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences &amp; School of Public Health, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid &amp; Cell Fate Regulation, Yangzhou University, Yangzhou, Jiangsu 225009, PR 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