ecDNA hubs drive cooperative intermolecular oncogene expression

King L. Hung, Kathryn E. Yost, Liangqi Xie, Quanming Shi, Konstantin Helmsauer, Jens Luebeck, Robert Schöpflin, Joshua T. Lange, Rocío Chamorro González, Natasha E. Weiser, Celine Chen, Maria E. Valieva, Ivy Tsz Lo Wong, Sihan Wu, Siavash R. Dehkordi, Connor V. Duffy, Katerina Kraft, Jun Tang, Julia A. Belk, John C. RoseM. Ryan Corces, Jeffrey M. Granja, Rui Li, Utkrisht Rajkumar, Jordan Friedlein, Anindya Bagchi, Ansuman T. Satpathy, Robert Tjian, Stefan Mundlos, Vineet Bafna, Anton G. Henssen, Paul S. Mischel, Zhe Liu, Howard Y. Chang

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs—clusters of around 10–100 ecDNAs within the nucleus—enable intermolecular enhancer–gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer–gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

Original languageEnglish (US)
Pages (from-to)731-736
Number of pages6
Issue number7890
StatePublished - Dec 23 2021

ASJC Scopus subject areas

  • General


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