Inhibition of human-HPV hybrid ecDNA enhancers reduces oncogene expression and tumor growth in oropharyngeal cancer
Extrachromosomal circular DNA (ecDNA) has been found in most types of human cancers, and ecDNA incorporating viral genomes has recently been described, specifically in human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC). However, the molecular mechanisms of human-viral hybrid ecDNA (hybrid ecDNA) for carcinogenesis remains elusive. We characterize the epigenetic status of hybrid ecDNA using HPVOPC cell lines and patient-derived tumor xenografts, identifying HPV oncogenes E6/E7 in hybrid ecDNA are flanked by previously unrecognized somatic DNA enhancers and HPV L1 enhancers, with strong cis-interactions. Targeting of these enhancers by clustered regularly interspaced short palindromic repeats interference or hybrid ecDNA by bromodomain and extra-terminal inhibitor reduces E6/E7 expression, and significantly inhibites in vitro and/or in vivo growth only in ecDNA(+) models. HPV DNA in hybrid ecDNA structures are associated with previously unrecognized somatic and HPV enhancers in hybrid ecDNA that drive HPV ongogene expression and carcinogenesis, and can be targeted with ecDNA disrupting therapeutics.
Authors
- Joseph A. Califano (ORCID: https://orcid.org/0000-0002-4715-6761)
- Takuya Nakagawa (ORCID: https://orcid.org/0000-0003-1216-4822)
- Vineet Bafna (ORCID: https://orcid.org/0000-0002-5810-6241)
- Abdula Monther
- Sara Javadzadeh (ORCID: https://orcid.org/0000-0001-8240-2860)
- Kersi Pestonjamasp (ORCID: https://orcid.org/0000-0001-8586-303X)
- Paul S. Mischel (ORCID: https://orcid.org/0000-0002-4560-2211)
- Roman Šášik (ORCID: https://orcid.org/0000-0002-9266-8993)
- Allen Wang (ORCID: https://orcid.org/0000-0001-9870-7888)
- Kathleen M. Fisch (ORCID: https://orcid.org/0000-0002-0117-7444)
- Jens Luebeck (ORCID: https://orcid.org/0000-0003-4391-979X)
- Sara Brin Rosenthal (ORCID: https://orcid.org/0000-0002-9072-8032)
- Joshua T. Lange (ORCID: https://orcid.org/0000-0002-4246-6058)
- Kaiyuan Zhu (ORCID: https://orcid.org/0009-0002-5167-1130)
- Chad Phillips
- Sayed Sadat
- Qian Yang
- Santiago Fassardi
Institutions
- Chiba Prefectural University of Health Sciences (JP)
- Chiba University (JP)
- UC San Diego Health System (US)
- University of California San Diego (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s41467-025-57447-9
- Citations
- 9
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 8.43
Funders
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- Japan Society for the Promotion of Science