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. Rose, M. 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 and Howard Y. Chang ()
Additional contact information
King L. Hung: Stanford University School of Medicine
Kathryn E. Yost: Stanford University School of Medicine
Liangqi Xie: Howard Hughes Medical Institute
Quanming Shi: Stanford University School of Medicine
Konstantin Helmsauer: Charité—Universitätsmedizin Berlin
Jens Luebeck: University of California, San Diego
Robert Schöpflin: Max Planck Institute for Molecular Genetics
Joshua T. Lange: University of California, San Diego
Rocío Chamorro González: Charité—Universitätsmedizin Berlin
Natasha E. Weiser: Stanford University School of Medicine
Celine Chen: Charité—Universitätsmedizin Berlin
Maria E. Valieva: Max Planck Institute for Molecular Genetics
Ivy Tsz-Lo Wong: Stanford University
Sihan Wu: University of Texas Southwestern Medical Center
Siavash R. Dehkordi: University of California, San Diego
Connor V. Duffy: Stanford University School of Medicine
Katerina Kraft: Stanford University School of Medicine
Jun Tang: Stanford University
Julia A. Belk: Stanford University
John C. Rose: Stanford University School of Medicine
M. Ryan Corces: Stanford University School of Medicine
Jeffrey M. Granja: Stanford University School of Medicine
Rui Li: Stanford University School of Medicine
Utkrisht Rajkumar: University of California, San Diego
Jordan Friedlein: Sanford Burnham Prebys Medical Discovery Institute
Anindya Bagchi: Sanford Burnham Prebys Medical Discovery Institute
Ansuman T. Satpathy: Stanford University
Robert Tjian: University of California, Berkeley
Stefan Mundlos: Max Planck Institute for Molecular Genetics
Vineet Bafna: University of California, San Diego
Anton G. Henssen: Charité—Universitätsmedizin Berlin
Paul S. Mischel: Stanford University
Zhe Liu: Howard Hughes Medical Institute
Howard Y. Chang: Stanford University School of Medicine

Nature, 2021, vol. 600, issue 7890, 731-736

Abstract: Abstract 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.

Date: 2021
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Citations: View citations in EconPapers (8)

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DOI: 10.1038/s41586-021-04116-8

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