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Peer-reviewedCC BY-NCScience Advances

Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21

  • Shiyi Yu1,2,3
  • Xue Gong4
  • Yawen Yang1,2,3
  • Ying Duan1,2,3
  • Siyu Zhang1,2,3
  • Ying Wang5
  • Zheng Wang6
  • Caili Bi1,2,3
  • Haibo Sun1,2,3
6 affiliations
  1. 1School 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.
  2. 2School 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.
  3. 3Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
  4. 4Nanjing Women and Children’s Healthcare Institute, Women’s Hospital of Nanjing Medical University, 123 Tianfei Alley, Mochou Road, Nanjing, Jiangsu 210004, PR China.
  5. 5Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
  6. 6Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225009, PR China.
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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.

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Cite

BibTeXRIS
BibTeX
@article{yu2026targeting,
  title = {{Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21}},
  author = {Shiyi Yu and Xue Gong and Yawen Yang and Ying Duan and Siyu Zhang and Ying Wang and Zheng Wang and Caili Bi and Haibo Sun},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aea2001},
  url = {https://www.science.org/doi/10.1126/sciadv.aea2001},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21
AU  - Shiyi Yu
AU  - Xue Gong
AU  - Yawen Yang
AU  - Ying Duan
AU  - Siyu Zhang
AU  - Ying Wang
AU  - Zheng Wang
AU  - Caili Bi
AU  - Haibo Sun
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aea2001
UR  - https://www.science.org/doi/10.1126/sciadv.aea2001
AB  - 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.
SN  - 2375-2548
ER  -