Skip to content
DraconiticResearch
Search Sources API
203,203 studies31 sourcesUpdated 42 min ago
Peer-reviewedCC BY 4.0Science Advances

METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression

  • Kanchan Kumari1,2
  • Iván Pérez-Núñez3
  • Aleix Noguera Castells4,5,6
  • Raquel Pluvinet7
  • Carlos Peula8
  • Annika Patthey9
  • Ghazala Naz Khan2,9
  • Kinga Pajdzik10
  • Ángel-Carlos Román11
  • Erik Dassi7
  • Chuan He10
  • Eva Lundin9
3 more authors
  • Manel Esteller6,12,13,14
  • Toni Celià-Terrassa3
  • Francesca Aguilo1,2
14 affiliations
  1. 1Department of Molecular Biology, Umeå University, SE-901 85 Umeå, Sweden.
  2. 2Wallenberg Centre for Molecular Medicine, Umeå University, SE-901 85 Umeå, Sweden.
  3. 3Cancer Research Program, Hospital del Mar Medical Research Institute (HMRI), Barcelona, Spain.
  4. 4Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
  5. 5Department of Biosciences, Faculty of Science, Technology and Engineering, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Barcelona, Catalonia, Spain.
  6. 6Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
  7. 7Genomics Unit, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
  8. 8Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
  9. 9Department of Medical Biosciences, Umeå University, SE-901 85 Umeå, Sweden.
  10. 10Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
  11. 11Department of Molecular Biology and Genetics, University of Extremadura, 06071 Badajoz, Spain.
  12. 12Cancer Epigenetics Group, Sant Pau Research Institute (IRSantPau), Barcelona, Catalonia, Spain.
  13. 13Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
  14. 14Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.
Read full textDOICite

Abstract

High-grade serous ovarian carcinoma (HGSOC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages and remains associated with poor clinical outcome. In this study, we identify a critical oncogenic role of the RNA methyltransferase METTL3 and the N6-methyladenosine (m6A) RNA modification pathway in HGSOC. Suppression of METTL3, either genetically or pharmacologically, and depletion of its binding partner METTL14 impair ovarian cancer proliferation and tumor progression. Mechanistically, we show that METTL3-mediated m6A deposition enhances the translation of DNA methyltransferase 1 (DNMT1), the primary maintenance DNA methyltransferase responsible for preserving genome-wide methylation patterns and silencing tumor suppressor genes. Pharmacological inhibition of DNMT1 induces widespread DNA hypomethylation and up-regulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 suppression reduces DNMT1 abundance and derepresses TNFAIP3 and FBXO32 expression. Knockdown and rescue studies further reveal that DNMT1 primarily mediates METTL3-dependent regulation of cell migration, whereas the antiproliferative effects of METTL3 suppression are likely driven by additional downstream targets. Collectively, these findings identify the m6A-METTL3-DNMT1 axis as a mechanistic link between RNA and DNA methylation pathways and a potential therapeutic vulnerability in HGSOC.

Related

  1. METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.
    Fajuan Tang, Hu Gao, Bin Chen +4
    Cell biology and toxicologyPeer-reviewedCC BY-NC-NDFull textMolecular biology & gene regulationEurope PMCPMC
  2. The Role of METTL3-Mediated m⁶A Methylation in Hepatocellular Carcinoma Progression and Treatment.
    Bala Gamage Nalaka Hasith Maduranga, Hee Doo Yang, Su In Lee +4
    EpigenomesPeer-reviewedCC BYFull textMolecular biology & gene regulationEurope PMC
  3. Characterization of METTL3/14-mediated m⁶A modification in human transcriptome using Nanopore direct RNA sequencing
    Emily Kurtyan, Andrew J. Stein, Kelly J. Abdalla +3
    PLOS GeneticsPeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationGenetics & genomicsPLOS
  4. METTL7B-Mediated m6A Modification of PLEKHA4 Suppresses Ferroptosis via Reducing AURKA Ubiquitination to Promote Papillary Thyroid Cancer Progression.
    Wei Lin, Kunlin Wu, Jinshu Chen +3
    Cancer medicinePeer-reviewedCC BY-NC-NDFull textMolecular biology & gene regulationEurope PMCPMC
  5. N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice
    Apoorva Verma, Nanyang Li, Pazhanichamy Kalailingam +4
    Frontiers in OncologyPeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationCrossrefEurope PMC

Cite

BibTeXRIS
BibTeX
@article{kumari2026mettl3mediated,
  title = {{METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression}},
  author = {Kanchan Kumari and Iván Pérez-Núñez and Aleix Noguera Castells and Raquel Pluvinet and Carlos Peula and Annika Patthey and Ghazala Naz Khan and Kinga Pajdzik and Ángel-Carlos Román and Erik Dassi and Chuan He and Eva Lundin and Manel Esteller and Toni Celià-Terrassa and Francesca Aguilo},
  journal = {Science Advances},
  year = {2026},
  month = nov,
  doi = {10.1126/sciadv.aec2297},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aec2297},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression
AU  - Kanchan Kumari
AU  - Iván Pérez-Núñez
AU  - Aleix Noguera Castells
AU  - Raquel Pluvinet
AU  - Carlos Peula
AU  - Annika Patthey
AU  - Ghazala Naz Khan
AU  - Kinga Pajdzik
AU  - Ángel-Carlos Román
AU  - Erik Dassi
AU  - Chuan He
AU  - Eva Lundin
AU  - Manel Esteller
AU  - Toni Celià-Terrassa
AU  - Francesca Aguilo
PY  - 2026
DA  - 2026/11/04
JO  - Science Advances
DO  - 10.1126/sciadv.aec2297
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aec2297
AB  - High-grade serous ovarian carcinoma (HGSOC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages and remains associated with poor clinical outcome. In this study, we identify a critical oncogenic role of the RNA methyltransferase METTL3 and the N6-methyladenosine (m6A) RNA modification pathway in HGSOC. Suppression of METTL3, either genetically or pharmacologically, and depletion of its binding partner METTL14 impair ovarian cancer proliferation and tumor progression. Mechanistically, we show that METTL3-mediated m6A deposition enhances the translation of DNA methyltransferase 1 (DNMT1), the primary maintenance DNA methyltransferase responsible for preserving genome-wide methylation patterns and silencing tumor suppressor genes. Pharmacological inhibition of DNMT1 induces widespread DNA hypomethylation and up-regulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 suppression reduces DNMT1 abundance and derepresses TNFAIP3 and FBXO32 expression. Knockdown and rescue studies further reveal that DNMT1 primarily mediates METTL3-dependent regulation of cell migration, whereas the antiproliferative effects of METTL3 suppression are likely driven by additional downstream targets. Collectively, these findings identify the m6A-METTL3-DNMT1 axis as a mechanistic link between RNA and DNA methylation pathways and a potential therapeutic vulnerability in HGSOC.
SN  - 2375-2548
ER  -