METTL3-mediated m 6 A modification of DNMT1 enhances ovarian cancer progression
Abstract High-grade serous carcinoma (HGSC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages owing to its asymptomatic progression and lack of early detection markers. In this study, we identified a critical oncogenic role of the RNA methyltransferase METTL3 and the N 6 -methyladenosine (m 6 A) RNA modification pathway in HGSC. Depletion of METTL3 or its binding partner METTL14 impairs ovarian cancer proliferation and tumor progression. Mechanistically, m 6 A deposition enhances the translation of DNA methyltransferase DNMT1, an epigenetic repressor that silences tumor suppressor genes. Pharmacologic inhibition of DNMT1 led to DNA hypomethylation and upregulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 depletion also increased the expression of these genes supporting a model in which METTL3 sustains oncogenesis by maintaining DNMT1 protein levels and repressing anti-tumor pathways. These findings position METTL3-mediated RNA modifications and DNMT1 as promising therapeutic targets in HGSC.
Authors
- Aleix Noguera‐Castells (ORCID: https://orcid.org/0000-0001-7436-6513)
- Kanchan Kumari (ORCID: https://orcid.org/0000-0001-7546-4174)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Ángel Román (ORCID: https://orcid.org/0000-0002-5868-6768)
- Annika Patthey
- Kinga Pajdzik (ORCID: https://orcid.org/0000-0003-2671-4004)
- Ghazala Naz Khan
- Raquel Pluvinet (ORCID: https://orcid.org/0000-0002-4955-8238)
- Toni Celià-Terrassa (ORCID: https://orcid.org/0000-0002-0615-8744)
- Iván Pérez-Núñez (ORCID: https://orcid.org/0000-0002-2907-1991)
- Erik Dassi (ORCID: https://orcid.org/0000-0003-4487-0449)
- Chuan He (ORCID: https://orcid.org/0000-0003-4319-7424)
- Francesca Aguiló (ORCID: https://orcid.org/0000-0002-2374-2045)
- Eva Lundin
- Carlos Peula
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of Trento (IT)
- University of Chicago (US)
- Josep Carreras Leukaemia Research Institute (ES)
- Hospital Del Mar (ES)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Hospital del Mar Research Institute (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
- Universidad de Extremadura (ES)
- Umeå University (SE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-11-04
- DOI
- https://doi.org/10.1126/sciadv.aec2297
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Kempe Foundation
- Cancerfonden
- Västerbotten Läns Landsting
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Umeå Universitet
- Cancer Research Foundation in Northern Sweden