Epigenetic profiling reveals key super-enhancer networks driving oncogenesis in HPV-positive HNSCC
Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is a growing subset of cancer cases distinct from HPV-negative by fewer genetic mutations and prevalent epigenetic dysregulation. We mapped H3K27ac-marked super-enhancers (SEs) via ChIP-seq in HPV+ patient-derived xenografts (PDXs) and normal oropharyngeal mucosa, identifying tumor-specific SE domains (T-SEDs) enriched for transcription factors (TFs) including TP63, FOSL1, and JUND. These SE-associated TFs regulate key oncogenic pathways and are downregulated by BRD4 inhibition with JQ1, highlighting sensitivity to epigenetic modulation. RNA-seq data revealed coordinated dysregulation of enhancer RNAs and mRNAs near T-SEDs, linked to upregulated pathways including epithelial-mesenchymal transition and E2F targets. JQ1 treatment significantly repressed these tumor-specific pathways, suggesting a therapeutic potential for targeting SE-driven transcription in HPV+ HNSCC. This study underscores the critical role of SEs in epigenetic and transcriptional dysregulation in HPV+ HNSCC, revealing therapeutic targets and providing a framework for future mechanistic studies in this area.
Authors
- Rossin Erbe (ORCID: https://orcid.org/0000-0002-3423-2104)
- Ilya E. Vorontsov (ORCID: https://orcid.org/0000-0001-8888-0804)
- Fernando T. Zamunér (ORCID: https://orcid.org/0000-0002-6106-4361)
- Theresa W. Guo (ORCID: https://orcid.org/0000-0002-1689-3275)
- Spencer S. Chan
- Eddie L. Imada (ORCID: https://orcid.org/0000-0001-9527-3703)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Ludmila Danilova (ORCID: https://orcid.org/0000-0003-2813-3094)
- Michael D. Kessler (ORCID: https://orcid.org/0000-0003-1258-5221)
- Daria A. Gaykalova (ORCID: https://orcid.org/0000-0001-5037-0147)
- Ivan V. Kulakovskiy (ORCID: https://orcid.org/0000-0002-6554-8128)
- Dong Xie (ORCID: https://orcid.org/0000-0002-1150-8657)
- Alexander V. Favorov (ORCID: https://orcid.org/0000-0003-2595-1091)
- Alexander Loginov
Institutions
- University of Maryland, Baltimore (US)
- University of Maryland Medical Center (US)
- Johns Hopkins University (US)
- Cornell University (US)
- Johns Hopkins Medicine (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
- Ufa Institute of Chemistry (RU)
- Institute of Protein Research (RU)
- Vavilov Institute of General Genetics (RU)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Weill Cornell Medicine (US)
- University of Maryland, College Park (US)
Publication Details
- Journal
- iScience
- Published
- 2025-10-30
- DOI
- https://doi.org/10.1016/j.isci.2025.113911
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81