{
  "abstract": "Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard therapies for estrogen receptor–positive 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 SUV39H2 drives its overexpression in CDK4/6i-resistant breast cancer cells. Clinically, elevated exon 2 inclusion in SUV39H2 correlates with poor prognosis in patients with breast cancer. Targeting SUV39H2 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 SUV39H2 promotes transcriptional activation of senescence-associated secretory phenotype genes, including p21 , 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.",
  "abstract_shown": true,
  "affiliations": [
    "School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.",
    "School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Integrated Traditional Chinese and Western Medicine in Senile Diseases Control, Yangzhou University, Yangzhou 225009, PR China.",
    "Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.",
    "Nanjing Women and Children’s Healthcare Institute, Women’s Hospital of Nanjing Medical University, 123 Tianfei Alley, Mochou Road, Nanjing, Jiangsu 210004, PR China.",
    "Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.",
    "Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225009, PR China."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Shiyi Yu",
      "orcid": "0000-0002-9926-852X"
    },
    {
      "affs": [
        3
      ],
      "name": "Xue Gong",
      "orcid": "0009-0006-2405-3192"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Yawen Yang",
      "orcid": "0009-0009-3170-6907"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ying Duan",
      "orcid": "0009-0002-1201-4453"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Siyu Zhang",
      "orcid": "0009-0006-5208-8253"
    },
    {
      "affs": [
        4
      ],
      "name": "Ying Wang"
    },
    {
      "affs": [
        5
      ],
      "name": "Zheng Wang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Caili Bi",
      "orcid": "0000-0003-1751-4377"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Haibo Sun",
      "orcid": "0000-0002-2946-8235"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a1m7x4vvg8587.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aea2001",
  "fulltext_url": null,
  "id": "a1m7x4vvg8587",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aea2001",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Advanced Breast Cancer Therapies"
    ]
  ],
  "openalex": "W7221189290",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-09",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/a1m7x4vvg8587.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aea2001",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aea2001"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Advanced Breast Cancer Therapies",
      "subfield": "general"
    }
  ],
  "title": "Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21",
  "title_text": "Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/a1m7x4vvg8587",
  "venue": "Science Advances",
  "versions": []
}