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Related Concept Videos

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ecDNA hubs drive cooperative intermolecular oncogene expression.

King L Hung1, Kathryn E Yost1, Liangqi Xie2,3,4

  • 1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.

Nature
|November 25, 2021
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Extrachromosomal DNA (ecDNA) hubs cluster together, enabling oncogenes to be overexpressed in cancer. A protein called BRD4 tethers these hubs, and inhibiting it reduces oncogene transcription, offering a potential cancer therapy target.

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Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Epigenetics

Background:

  • Extrachromosomal DNA (ecDNA) is common in human cancers, driving oncogene overexpression via gene amplification and regulatory changes.
  • Intra-chromosomal gene regulation typically relies on cis-regulatory elements contacting genes on the same chromosome.

Purpose of the Study:

  • To investigate the role of ecDNA hubs in promoting oncogene overexpression.
  • To identify the mechanisms and proteins involved in ecDNA hub formation and function.
  • To explore ecDNA hubs as potential therapeutic targets in cancer.

Main Methods:

  • Observation of ecDNA hub formation in diverse cancer cell types and tumors.
  • Utilizing BRD4 inhibition (JQ1) to study its effect on ecDNA hubs and oncogene transcription.
  • Employing CRISPR interference to systematically silence ecDNA enhancers.
  • Investigating intermolecular enhancer-gene interactions mediated by ecDNA hubs.

Main Results:

  • ecDNA hubs, clusters of 10-100 ecDNAs, facilitate intermolecular enhancer-gene interactions, boosting oncogene expression.
  • BRD4 protein tethers ecDNA hubs, and its inhibition disperses hubs and reduces oncogene transcription.
  • The PVT1 promoter fused to MYC on ecDNA receives broad enhancer input, driving potent MYC expression.
  • Intermolecular enhancer-gene activation occurs among multiple oncogenes amplified on distinct ecDNAs within hubs.

Conclusions:

  • Protein-tethered ecDNA hubs enable intermolecular transcriptional regulation, acting as units of oncogene function and cooperative evolution.
  • Targeting ecDNA hubs with inhibitors like JQ1 offers a promising strategy for cancer therapy.