Nakagawa Takuya, Luebeck Jens, Zhu Kaiyuan, Lange Joshua T, Sasik Roman, Phillips Chad, Sadat Sayed, Javadzadeh Sara, Yang Qian, Monther Abdula, Fassardi Santiago, Wang Allen, Pestonjamasp Kersi, Rosenthal Brin, Fisch Kathleen M, Mischel Paul, Bafna Vineet, Califano Joseph A
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.
Nat Commun. 2025 Mar 26;16(1):2964. doi: 10.1038/s41467-025-57447-9.
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.
在大多数类型的人类癌症中都发现了染色体外环状DNA（ecDNA），并且最近有报道称ecDNA整合了病毒基因组，特别是在人乳头瘤病毒（HPV）介导的口咽癌（OPC）中。然而，人类-病毒杂交ecDNA（杂交ecDNA）致癌的分子机制仍不清楚。我们使用HPVOPC细胞系和患者来源的肿瘤异种移植物来表征杂交ecDNA的表观遗传状态，发现杂交ecDNA中的HPV癌基因E6/E7两侧是以前未被识别的体细胞DNA增强子和HPV L1增强子，具有很强的顺式相互作用。通过成簇规律间隔短回文重复序列干扰靶向这些增强子或通过溴结构域和额外末端抑制剂靶向杂交ecDNA可降低E6/E7表达，并且仅在ecDNA（+）模型中显著抑制体外和/或体内生长。杂交ecDNA结构中的HPV DNA与杂交ecDNA中以前未被识别的体细胞和HPV增强子相关，这些增强子驱动HPV癌基因表达和致癌作用，并且可以用破坏ecDNA的疗法进行靶向治疗。
