2. Academic Validation
  3. Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition

Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition

  • Proc Natl Acad Sci U S A. 2025 Dec 30;122(52):e2516667122. doi: 10.1073/pnas.2516667122.
Joseph L Collura 1,  Kuan Cheok Lei 2 3,  Mitalee Chandra 2,  Thibault Kervarrec 4,  Hyun Jung Park 5,  Mazdak Dalkoohi 2,  Jürgen C Becker 2 3,  Yuan Chang 1 6,  Patrick S Moore 1 6,  Masahiro Shuda 1 6
Affiliations

Affiliations

  • 1 Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213.
  • 2 Translational Skin Cancer Research, German Cancer Consortium, University Medicine Essen, Essen 45141, Germany.
  • 3 German Cancer Consortium, German Cancer Research Center, Heidelberg 69129, Germany.
  • 4 "Biologie des infections à polyomavirus" Team, Université de Tours, Tours 37380, France.
  • 5 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15260.
  • 6 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261.
PMID: 41439710 DOI: 10.1073/pnas.2516667122
Abstract

Merkel cell polyomavirus (MCV) T antigen functions as an oncoprotein that drives the transformation of Merkel cell carcinoma (MCC) cells by activating transcription factors involved in cell proliferation. The viral T antigen promoter requires the activity of the cellular coactivator CREB-binding protein (CBP)/p300 for its expression. Inhibition of CBP/p300 with two distinct small-molecule inhibitors suppresses T antigen expression, leading to cell cycle arrest and upregulation of the cell cycle inhibitor p27Kip1. This shift promotes neuronal differentiation, associated with neurite outgrowth in MCC cells. RNA Sequencing revealed downregulation of genes involved in E2F, Myc, mTORC1 oncogenic signaling, as well as markers of the Merkel cell lineage including Sox2 and Atoh1. Notably, a rare MCC case exhibiting a mixed cellular composition, with loss of T antigen expression and neuroblastic phenotype, showed a transcriptomic profile resembling that of MCC cells treated with CBP/p300 inhibitors. This suggests that similar differentiation processes may contribute to tumor heterogeneity in patients. This study presents the model system enabling reversible switching between a transformed and differentiated cell state in a human Cancer using small-molecule treatment.

Keywords

CBP/p300; Merkel cell carcinoma; Merkel cell polyomavirus; T antigen; cancer reversion.

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