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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-boundPVT1 promoter is
ectopically fused to MYCand duplicated in ecDNA, receiving promiscuous enhancer
input to drive potent expression of MYC. Furthermore, the PVT1promoter 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.
