ESM1 mediated DNMT3A suppresses cervical cancer metastasis by epigenetic regulation of ID3 Expression

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 oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. the epigenetic mechanisms sustaining 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 reveal marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies demonstrate that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling uncovers ID3 as a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates 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 validate that ESM1 depletion significantly impairs 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.