Extrachromosomal DNA associates with nuclear condensates and reorganizes chromatin structures to enhance oncogenic transcription.
Document Type
Article
Publication Date
12-8-2025
Original Citation
Taghbalout A,
Tung C,
Clow P,
Tjong H,
Wang P,
Wong C,
Mao D,
Maurya R,
Huang M,
Ngan C,
Kim A,
Wei C.
Extrachromosomal DNA associates with nuclear condensates and reorganizes chromatin structures to enhance oncogenic transcription. Cancer Cell. 2025;43(12):2191–205 e6.
Keywords
JGM, SS1, Humans, Chromatin, Transcription, Genetic, DNA, Circular, Neoplasms, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Cell Nucleus, Epigenesis, Genetic, Carcinogenesis, Animals, Oncogenes, Mice
JAX Source
Cancer Cell. 2025;43(12):2191–205 e6.
ISSN
1878-3686
PMID
40972571
DOI
https://doi.org/10.1016/j.ccell.2025.08.008
Abstract
Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting nuclear condensates breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans-activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for alternative therapeutic strategies in cancer treatment.