Miao, Lingling, Milewski, David, Coxon, Amy, Gelb, Tara, Garman, Khalid A, Porch, Jadon, Khanna, Arushi, Collado, Loren, Hill, Natasha T, Daily, Kenneth, Vilasi, Serena, Reed, Danielle, Alexander, Tiffany, Starrett, Gabriel J, Chakraborty, Maharshi, Song, Young, Choi, Rachel, Gangalapudi, Vineela, Seaman, Josiah, Morton, Andrew, Busam, Klaus J, Vakoc, Christopher R, Urban, Daniel J, Shen, Min, Hall, Matthew D, Sallari, Richard, Khan, Javed, Gryder, Berkley E, Brownell, Isaac (December 2025) Interlocking host and viral cis-regulatory networks drive Merkel cell carcinoma. Journal of Clinical Investigation, 135 (24). ISSN 1558-8238
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders diseases & disorders > neoplasms |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 15 December 2025 |
| Date Deposited: | 22 Dec 2025 13:36 |
| Last Modified: | 22 Dec 2025 13:36 |
| PMCID: | PMC12700541 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42047 |
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