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Peer-reviewedCC BY 4.0Cell Death Discovery

ESM1-mediated DNMT3A suppresses cervical cancer metastasis through epigenetic regulation of ID3 expression

  • Chen-Lin Yu1,2
  • Chia-Liang Lin3,4
  • Hsiang-Lin Lee5,6
  • Hui-Ling Chiou7
  • Pei-Ni Chen8,9
  • Shun-Fa Yang8,9
  • Yi-Hsien Hsieh8,9
9 affiliations
  1. 1Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan
  2. 2Institute of Biomedical Sciences, MacKay Medical University, New Taipei City, Taiwan
  3. 3Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
  4. 4Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
  5. 5Deptartment of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
  6. 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan
  7. 7School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
  8. 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
  9. 9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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Abstract

Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.

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Cite

BibTeXRIS
BibTeX
@article{yu2026esm1mediated,
  title = {{ESM1-mediated DNMT3A suppresses cervical cancer metastasis through epigenetic regulation of ID3 expression}},
  author = {Chen-Lin Yu and Chia-Liang Lin and Hsiang-Lin Lee and Hui-Ling Chiou and Pei-Ni Chen and Shun-Fa Yang and Yi-Hsien Hsieh},
  journal = {Cell Death Discovery},
  year = {2026},
  month = aug,
  doi = {10.1038/s41420-026-03239-z},
  url = {https://doi.org/10.1038/s41420-026-03239-z},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - ESM1-mediated DNMT3A suppresses cervical cancer metastasis through epigenetic regulation of ID3 expression
AU  - Chen-Lin Yu
AU  - Chia-Liang Lin
AU  - Hsiang-Lin Lee
AU  - Hui-Ling Chiou
AU  - Pei-Ni Chen
AU  - Shun-Fa Yang
AU  - Yi-Hsien Hsieh
PY  - 2026
DA  - 2026/08/07
JO  - Cell Death Discovery
DO  - 10.1038/s41420-026-03239-z
UR  - https://doi.org/10.1038/s41420-026-03239-z
AB  - Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
SN  - 2058-7716
ER  -