ArticleClinical epigenetics2020
DNA methylation-driven EMT is a common mechanism of resistance to various therapeutic agents in cancer.
Article in Clinical epigenetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 103 citations in OpenAlex.
- Molecular mechanisms and therapeutic strategies: DNA methylation in pancreatic cancer.Cancer biology & therapy · 2026Review
- Epigenetic reprogramming of lineage switching in cancer.FEBS letters · 2026Review
- Tracking breast cancer progression using Methylscape.Science advances · 2026Article
- A clinical decision framework for redox-adapted, EMT-high cancers: From ferroptosis resistance to precision therapeutic stratification.Redox biology · 2026Review
- The crosstalk between epigenetics and metabolism in the malignant cell.Discover oncology · 2026Review
- Longitudinal cell-free DNA methylome and fragmentome profiles in health uncover signatures of cell type and demographic origin.Genome medicine · 2026Article
- Article
- Atherosclerotic Fibrous Plaques in Women Present ECM Remodeling Linked to TGF-β.Circulation research · 2026Article
- Tumor-based biomarkers and circulating tumor DNA for precision medicine in advanced hepatocellular carcinoma.Clinical and molecular hepatology · 2026Review
- Design and Validation of a Predictive Model for Hepatocellular Carcinoma Based on Genes With Differential Expression Driven by DNA Methylation.International journal of genomics · 2026Article
- Integrator Complex Subunit 6 Regulates Biological Nature of Hepatocellular Carcinoma by Modulating Epithelial-Mesenchymal Transition.Current issues in molecular biology · 2025Article
- Multi-modal characterization of transcriptional programs that drive metastatic cascades to solid sites and ascites in ovarian cancer.bioRxiv : the preprint server for biology · 2025Article
- Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.Cell death & disease · 2025Article
- Exploring genome-transcriptome correlations in cancer.Biochemical Society transactions · 2025Review
- Schwann cell reprogramming via EMT-like program following peripheral nerve injury and during nerve regeneration.Frontiers in cell and developmental biology · 2025Review
- Nanocomposites to Overcoming Sorafenib Resistance in Hepatocellular Carcinoma Therapy.International journal of nanomedicine · 2025Review
- Nanotechnology in cancer treatment: revolutionizing strategies against drug resistance.Frontiers in bioengineering and biotechnology · 2025Review
- DNA methylation and immune evasion in triple-negative breast cancer: challenges and therapeutic opportunities.Frontiers in oncology · 2025Review
- Epithelial-mesenchymal dynamics in cancer: Role of signalling pathways, stromal interactions and natural therapies.ADMET & DMPK · 2025Review
- Comprehensive review and updated analysis of DNA methylation in hepatocellular carcinoma: From basic research to clinical application.Clinical and translational medicine · 2024Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundOvercoming therapeutic resistance is one of the major hurdles in cancer care. One mechanism contributing to therapeutic resistance is a process in which epithelial cells switch to a mesenchymal state (epithelial-to-mesenchymal transition or EMT). The precise mechanisms driving EMT-mediated therapeutic resistance have, however, not been elucidated.
resultsHere, we study ten cell line pairs, for which parental cell lines were made resistant to either a targeted or chemotherapy-based treatment. First, we show by miRNA-200 overexpression that treatment resistance is driven by EMT. Next, we demonstrate that DNA methylation changes occur within each cell line pair and show that exposure to 5-azacytidine or knock down of DNA methyltransferases (DNMTs), both of which globally demethylate cells, result in EMT reversal and increased therapeutic sensitivity. This suggests DNA methylation to causally underlie EMT and treatment resistance. We also observe significant overlap in methylation profiles between resistant lines, suggesting a common epigenetic mechanism to cause resistance to therapy. In line with this hypothesis, cross-resistance to other targeted and chemotherapies is observed, while importantly, this is lost upon demethylation of the cells. Finally, we clinically validate that DNA methylation changes drive EMT-mediated resistance to sorafenib in patients with advanced hepatocellular carcinoma (HCC). Specifically, we develop a capture-based protocol to interrogate DNA methylation in low amounts of circulating tumor DNA (ctDNA). By interrogating the methylation status in liquid biopsies, longitudinally collected during sorafenib treatment, we assess whether DNA methylation changes also drive EMT and therapy resistance in a clinical setting. Particularly, by monitoring methylation changes in EMT genes, we are able to predict tumor response and acquired resistance to sorafenib.
conclusionsWe propose methylation changes underlying EMT to constitute a common resistance mechanism to cancer therapies. This process can be reversed pharmacologically and monitored non-invasively in ctDNA to predict resistance to treatment.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.