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ecDNA hubs drive cooperative intermolecular oncogene expression

Item Type:Article
Title:ecDNA hubs drive cooperative intermolecular oncogene expression
Creators Name:Hung, K.L. and Yost, K.E. and Xie, L. and Shi, Q. and Helmsauer, K. and Luebeck, J. and Schöpflin, R. and Lange, J.T. and Chamorro González, R. and Weiser, N.E. and Chen, C. and Valieva, M.E. and Wong, I.T.L. and Wu, S. and Dehkordi, S.R. and Duffy, C.V. and Kraft, K. and Tang, J. and Belk, J.A. and Rose, J.C. and Corces, M.R. and Granja, J.M. and Li, R. and Rajkumar, U. and Friedlein, J. and Bagchi, A. and Satpathy, A.T. and Tjian, R. and Mundlos, S. and Bafna, V. and Henssen, A.G. and Mischel, P.S. and Liu, Z. and Chang, H.Y.
Abstract:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. 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.
Keywords:Azepines, Cell Cycle Proteins, Tumor Cell Line, Gene Amplification, Neoplastic Gene Expression Regulation, Neoplasms, Nuclear Proteins, Oncogenes, Transcription Factors
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Volume:600
Number:7890
Page Range:731-736
Date:23 December 2021
Official Publication:https://doi.org/10.1038/s41586-021-04116-8
PubMed:View item in PubMed

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