Journal Article

DKFZ-2025-03054

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition.

Collura, J. L. ; Lei, K. C.DKFZ* ; Chandra, M. ; Kervarrec, T. ; Park, H. J. ; Dalkoohi, M. ; Becker, J.DKFZ* ; Chang, Y. ; Moore, P. S. ; Shuda, M.

2025
National Acad. of Sciences Washington, DC

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.

Keyword(s): Carcinoma, Merkel Cell: drug therapy (MeSH) ; Carcinoma, Merkel Cell: metabolism (MeSH) ; Carcinoma, Merkel Cell: pathology (MeSH) ; Carcinoma, Merkel Cell: genetics (MeSH) ; Carcinoma, Merkel Cell: virology (MeSH) ; Humans (MeSH) ; Merkel cell polyomavirus: metabolism (MeSH) ; E1A-Associated p300 Protein: antagonists & inhibitors (MeSH) ; E1A-Associated p300 Protein: metabolism (MeSH) ; CREB-Binding Protein: antagonists & inhibitors (MeSH) ; CREB-Binding Protein: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Gene Expression Regulation, Neoplastic: drug effects (MeSH) ; Skin Neoplasms: drug therapy (MeSH) ; Skin Neoplasms: metabolism (MeSH) ; Skin Neoplasms: pathology (MeSH) ; Skin Neoplasms: genetics (MeSH) ; Antigens, Viral, Tumor: metabolism (MeSH) ; Antigens, Viral, Tumor: genetics (MeSH) ; Cell Proliferation: drug effects (MeSH) ; Cell Differentiation: drug effects (MeSH) ; p300-CBP Transcription Factors: antagonists & inhibitors (MeSH) ; p300-CBP Transcription Factors: metabolism (MeSH) ; CBP/p300 ; Merkel cell carcinoma ; Merkel cell polyomavirus ; T antigen ; cancer reversion ; E1A-Associated p300 Protein ; CREB-Binding Protein ; EP300 protein, human ; CREBBP protein, human ; Antigens, Viral, Tumor ; p300-CBP Transcription Factors

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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