Extrachromosomal DNAs are free floating donuts of DNA found in nearly half of all types of tumors that encode multiple copies of oncogenes and play a major role in tumor growth, evolution and drug resistance. Researchers led by Ludwig Stanford’s Howard Chang reported in Nature in November that ecDNAs act as a collective, huddling in hubs of 10-100 in the nuclei of cancer cells. Howard and his colleagues discovered that this clustering enables a surprising phenomenon called “intermolecular gene activation,” in which enhancer sequences from one molecule of ecDNA can amplify the expression of oncogenes on other ecDNA molecules, dramatically boosting oncogene expression in a manner never seen on chromosomes. The researchers report that the hubs are tethered together by the bromodomain and extraterminal domain (BET) protein BRD4, and that the BET inhibitor JQ1 breaks up the hubs and inhibits the expression of their oncogenes. They found that, in a MYC amplified colorectal cancer cell line, MYC oncogene is fused to a duplicated promoter that receives multiple enhancer signals and is thus expressed at extremely high levels. Their findings demonstrate that ecDNA hubs serve as units of oncogene function and cooperative evolution, and could be sound drug targets for cancer therapy.
This article appeared in the May 2022 issue of Ludwig Link. Click here to download a copy (PDF, 2MB).