ArticleGenome biology2022
METTL4-mediated nuclear N6-deoxyadenosine methylation promotes metastasis through activating multiple metastasis-inducing targets.
Article in Genome biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- LINC01857 promotes clear cell renal cell carcinoma progression by scaffolding DNMT1 to suppress WIF1 expression.Scientific reports · 2026Article
- Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.Nucleic acids research · 2026Article
- N6-adenosine methyltransferase METTL4 is a potential prognostic biomarker and associates with cell cycle regulation and immune infiltration in glioma.Translational cancer research · 2025Article
- Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter.Experimental hematology & oncology · 2025Article
- Linking oxysterols and different stages of mild cognitive impairment: insights from gut metabolites and N6-methyladenosine.Alzheimer's research & therapy · 2025Article
- Correlation of METTL4 genetic variants and severe pneumonia pediatric patients in Southern China.BMC genomic data · 2025Article
- Article
- ALKBH4 functions as a hypoxia-responsive tumor suppressor and inhibits metastasis and tumorigenesis.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment.Cell death and differentiation · 2025Article
- miR-378d suppresses gastric cancer metastasis by targeting METTL4 to inhibit epithelial-mesenchymal transition.Journal of molecular histology · 2025Article
- Cis-Regulation of an mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- METTL4 and METTL5 as biomarkers for recurrence-free survival in hepatocellular carcinoma patients.Future oncology (London, England) · 2025Article
- Review of the role and potential clinical value of m6A methylation modifications in the biological process of osteosarcoma.Frontiers in genetics · 2025Review
- New perspectives on DNA methylation modifications in ocular diseases.International journal of ophthalmology · 2025Review
- Crosstalk between hypoxia-inducible factor (HIF) and lncRNAs in digestive tumors: from molecular mechanisms to clinical translation.Frontiers in cell and developmental biology · 2025Review
- Interrogation of the interplay between DNA N6-methyladenosine (6mA) and hypoxia-induced chromatin accessibility by a randomized empirical model (EnrichShuf).Nucleic acids research · 2024Article
- RNA m6A methylation regulatory mechanism of resveratrol in premature senescence cells.Food science & nutrition · 2024Article
- Inhibition of METTL4: Targeting a Methyltransferase that Alleviates Heart Failure by Modulating Excess N6-Methyladenine in Mitochondrial DNA.Journal of cardiovascular translational research · 2024Article
- Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma.Biomarker research · 2024Article
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Authors and funding
16 authors at 8 institutions in 3 countries.
Funding
Abstract
backgroundDNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.
resultsHere we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.
conclusionsWe show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.
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