Inhibition of novel human-HPV hybrid ecDNA enhancers reduces oncogene expression and tumor growth in oropharyngeal cancer.

Autor:	Nakagawa T; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.; Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan.; Health and Disease Omics Center, Chiba University, Chiba, Japan., Luebeck J; Department of Computer Science and Engineering, UC San Diego, La Jolla, CA, USA., Zhu K; Department of Computer Science and Engineering, UC San Diego, La Jolla, CA, USA., Lange JT; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Sasik R; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA, USA., Phillips C; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Sadat S; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Javadzadeh S; Department of Computer Science and Engineering, UC San Diego, La Jolla, CA, USA., Yang Q; Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., Wang A; Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., Pestonjamasp K; Cancer Center Microscopy Core, University of California, San Diego, La Jolla, CA, USA., Rosenthal B; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA, USA., Fisch KM; Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, CA, USA., Mischel P; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Bafna V; Department of Computer Science and Engineering, UC San Diego, La Jolla, CA, USA., Califano JA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.; Department of Otolaryngology - Head and Neck Surgery, University of California, San Diego, La Jolla, CA, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Sep 05. Date of Electronic Publication: 2024 Sep 05.
DOI:	10.21203/rs.3.rs-4636308/v1
Abstrakt:	Extrachromosomal circular DNA (ecDNA) have 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 characterized the epigenetic status of hybrid ecDNA using HPVOPC cell lines and patient-derived tumor xenografts, identifying HPV oncogenes E6/E7 in hybrid ecDNA were flanked by novel somatic DNA enhancers and HPV L1 enhancers, with strong cis-interaction. Targeting of these enhancers by clustered regularly interspaced short palindromic repeats interference or hybrid ecDNA by bromodomain and extra-terminal inhibitor reduced E6/E7 expression, and significantly inhibited in vitro and/or in vivo growth only in ecDNA(+) models. HPV DNA in hybrid ecDNA structures are associated with novel somatic and HPV enhancers in hybrid ecDNA that drive HPV ongogene expression and carcinogenesis, and can be targeted with ecDNA disrupting therapeutics. Competing Interests: Conflict of interest: P.S.M. is a co-founder, chairs the scientific advisory board (SAB) of and has equity interest in Boundless Bio Inc. (BBI). P.S.M. is also an advisor with equity for Asteroid Therapeutics and is an advisor to Sage Therapeutics. V.B. is a co-founder, consultant, SAB member and has equity interest in Boundless Bio and Abterra. J.T.L is an employee of BBI. J.L. previously consulted for BBI. The other authors have no conflicts of interest to disclose.
Databáze:	MEDLINE
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