Interlocking host and viral cis-regulatory networks drive Merkel cell carcinoma
Over 15% of cancers worldwide are caused by viruses. Merkel cell polyomavirus (MCPyV) is the most recently discovered human oncovirus and is the only polyomavirus that drives malignant tumors in humans. Here, we show that MCPyV+ Merkel cell carcinoma is defined by neuroendocrine-lineage core regulatory (CR) transcription factors (TFs) (ATOH1, INSM1, ISL1, LHX3, POU4F3, and SOX2) that were essential for tumor survival and that co-bound chromatin with the viral small T antigen at super enhancers. Moreover, MCPyV integration sites were enriched at these neuroendocrine super enhancers. We further discovered that the MCPyV noncoding control region contained a homeodomain binding motif absent in other polyomaviruses that bound ISL1 and LHX3 and depended on them for T antigen expression. To therapeutically target the CR factors, we used histone deacetylase (HDAC) inhibitors to collapse the chromatin architecture and induce topological blurring of superenhancer loops, abrogating core TF expression and halting tumor growth. To our knowledge, our study presents the first example of oncogenic cross-regulation between viral and human epigenomic circuitry to generate interlocking and essential transcriptional feedback circuits that explain why MCPyV causes neuroendocrine cancer and represent a tumor dependency that can be targeted therapeutically.
Authors
- Natasha T. Hill (ORCID: https://orcid.org/0000-0001-9043-4643)
- Khalid A. Garman (ORCID: https://orcid.org/0000-0003-3818-5939)
- Tara Gelb (ORCID: https://orcid.org/0000-0003-1811-8448)
- Gabriel J. Starrett (ORCID: https://orcid.org/0000-0001-5871-5306)
- Jadon Porch
- Christopher R. Vakoc (ORCID: https://orcid.org/0000-0002-1158-7180)
- Javed Khan (ORCID: https://orcid.org/0000-0002-5858-0488)
- Matthew D. Hall (ORCID: https://orcid.org/0000-0002-5073-442X)
- Loren Collado (ORCID: https://orcid.org/0000-0001-8251-6737)
- Klaus J. Busam (ORCID: https://orcid.org/0000-0003-0888-9601)
- Richard Sallari (ORCID: https://orcid.org/0000-0002-5519-2965)
- Tiffany Alexander
- Isaac Brownell (ORCID: https://orcid.org/0000-0002-0090-9914)
- Amy Coxon
- Maharshi Chakraborty (ORCID: https://orcid.org/0000-0003-2898-4710)
- Kenneth Daily (ORCID: https://orcid.org/0000-0001-5729-7376)
- Vineela Gangalapudi
- Andrew R. Morton (ORCID: https://orcid.org/0000-0002-1234-1676)
- Danielle Reed (ORCID: https://orcid.org/0000-0002-4264-8935)
- David Milewski (ORCID: https://orcid.org/0000-0002-9778-8548)
- Daniel J. Urban (ORCID: https://orcid.org/0000-0002-2672-8468)
- Lingling Miao (ORCID: https://orcid.org/0000-0003-3674-2885)
- Min Shen (ORCID: https://orcid.org/0000-0002-8218-0433)
- Young Song (ORCID: https://orcid.org/0000-0003-0580-1600)
- Rachel Choi (ORCID: https://orcid.org/0009-0001-6075-8687)
- Berkley E. Gryder (ORCID: https://orcid.org/0000-0003-0130-2302)
- Jill Seaman
- Serena Vilasi (ORCID: https://orcid.org/0000-0002-6887-3532)
- Arushi Khanna
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
- AnywherEnergy (United States) (US)
- National Cancer Institute (US)
- National Center for Advancing Translational Sciences (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1172/jci188924
- Citations
- 2
- Primary Topic
- Polyomavirus and related diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.09