{"id":348,"title":"METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression","title_zh":"METTL3介导的m6A修饰增强DNMT1翻译并促进高级别浆液性卵巢癌进展","url":"https://pubmed.ncbi.nlm.nih.gov/42981409","doi":"10.1126/sciadv.aec2297","pmid":"42981409","journal":"Sci Adv","kind":"paper","lang":"en","published_at":"2026-11-04T00:00:00+00:00","fetched_at":"2026-11-08T03:44:12+00:00","authors":["Kumari K","Pérez-Núñez I","Noguera Castells A","Pluvinet R","Peula C","Patthey A","Khan GN","Pajdzik K","Román ÁC","Dassi E","He C","Lundin E","Esteller M","Celià-Terrassa T","Aguilo F"],"primary_topic":"oocyte","topics":[{"slug":"oocyte","score":4.0,"hits":["ovarian"]},{"slug":"repro-genetics","score":1.0,"hits":["dna methylation"]},{"slug":"ethics-policy","score":1.0,"hits":["regulation"]}],"topic_score":4.0,"preference_score":0.0,"preference_labels":[],"llm_score":53.0,"final_score":61.0,"score_dims":{"novelty":72,"rigor":78,"impact":45,"relevance":22,"translation":30},"recommend_reason":"机制清晰、发表于Sci Adv，对表观遗传（m6A与DNA甲基化交叉调控）读者有价值；但研究对象为卵巢上皮性癌，与卵母细胞、胚胎及辅助生殖临床基本无关，非生殖医学核心内容，仅可作表观遗传机制参考。","keywords":["METTL3","m6A","DNMT1","高级别浆液性卵巢癌","表观遗传调控"],"selected":1,"story_id":74,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-top-journals","source_name":"PubMed · CNS/大子刊/四大医学刊（生殖相关）","source_tier":1,"mention_count":2,"has_interpretation":false,"journal_key":"sci-adv","journal_tier":"cns-sub","journal_if":11.7,"is_mock":false,"summary_zh":"该研究以高级别浆液性卵巢癌（HGSOC）为对象，探讨RNA甲基转移酶METTL3及其m6A修饰通路的作用。遗传学或药物抑制METTL3、以及敲低其结合伙伴METTL14，均可抑制卵巢癌细胞增殖与肿瘤进展。机制上，METTL3介导的m6A沉积增强维持性DNA甲基转移酶DNMT1的翻译；抑制DNMT1引起全基因组DNA低甲基化，并上调抑癌基因TNFAIP3与FBXO32。敲低与回补实验显示，DNMT1主要介导METTL3依赖的细胞迁移调控，而抗增殖效应可能由其他下游靶点驱动。作者据此提出m6A-METTL3-DNMT1轴连接RNA与DNA甲基化通路，是HGSOC的潜在治疗靶点。","summary":"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.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}