ArticleNucleic acids research2025
The NEXT complex regulates H3K27me3 levels to affect cancer progression by degrading G4/U-rich lncRNAs.
Article in Nucleic acids research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Epigenetics in lung cancer precision medicine: from bench to bedside-a narrative review.Translational lung cancer research · 2026Review
- Review
- H3K4me3 and H3K27ac Promote ccRCC Proliferation Through the CDC6-EXOSC5 Axis.International journal of molecular sciences · 2026Article
- Long Non-Coding RNAs in Pathogenesis of Renal Cell Carcinoma: Epigenetic Regulation, Signaling Pathways, and Therapeutic Strategies.International journal of molecular sciences · 2026Review
- Targeting the TRIM25-AGO2-miR-148b-5p-ABCC1 axis overcomes chemoresistance in non-small cell lung cancer.Cell death & disease · 2026Article
- Tumor exosomes impact functional hallmarks of cancer.Cancer metastasis reviews · 2026Review
- Bridging the Gap in Breast Cancer Dormancy: Models, Mechanisms, and Translational Challenges.Pharmaceuticals (Basel, Switzerland) · 2025Review
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Authors and funding
19 authors.
Funding
Abstract
Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous noncoding RNAs in the nucleoplasm. Here we find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels. Specifically, ZCCHC8 depletion results in significant upregulation of nascent long noncoding RNAs (lncRNAs) containing G-quadruplex (G4) and U-Rich motifs (G4/U-Rich lncRNAs). The G4 motif binds to EZH2, blocking the chromatin recruitment of PRC2, while the U-Rich motif is specifically recognized by the NEXT complex for RNA exosome-mediated degradation. In tumor tissues with high ZCCHC8 expression in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patients, the NEXT complex excessively degrades nascent G4/U-Rich lncRNAs. Consequently, PRC2 core subunits are released and recruited to neighboring genomic loci, resulting in increased H3K27me3 levels and downregulation of adjacent genes, including tumor suppressors like SEMA5A and ARID1A. Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading nascent G4/U-Rich lncRNAs in cancer cells.
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