TY  - JOUR
AU  - Collura, Joseph L
AU  - Lei, Kuan Cheok
AU  - Chandra, Mitalee
AU  - Kervarrec, Thibault
AU  - Park, Hyun Jung
AU  - Dalkoohi, Mazdak
AU  - Becker, Jürgen
AU  - Chang, Yuan
AU  - Moore, Patrick S
AU  - Shuda, Masahiro
TI  - Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 122
IS  - 52
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2025-03054
SP  - e2516667122
PY  - 2025
AB  - 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.
KW  - Carcinoma, Merkel Cell: drug therapy
KW  - Carcinoma, Merkel Cell: metabolism
KW  - Carcinoma, Merkel Cell: pathology
KW  - Carcinoma, Merkel Cell: genetics
KW  - Carcinoma, Merkel Cell: virology
KW  - Humans
KW  - Merkel cell polyomavirus: metabolism
KW  - E1A-Associated p300 Protein: antagonists & inhibitors
KW  - E1A-Associated p300 Protein: metabolism
KW  - CREB-Binding Protein: antagonists & inhibitors
KW  - CREB-Binding Protein: metabolism
KW  - Cell Line, Tumor
KW  - Gene Expression Regulation, Neoplastic: drug effects
KW  - Skin Neoplasms: drug therapy
KW  - Skin Neoplasms: metabolism
KW  - Skin Neoplasms: pathology
KW  - Skin Neoplasms: genetics
KW  - Antigens, Viral, Tumor: metabolism
KW  - Antigens, Viral, Tumor: genetics
KW  - Cell Proliferation: drug effects
KW  - Cell Differentiation: drug effects
KW  - p300-CBP Transcription Factors: antagonists & inhibitors
KW  - p300-CBP Transcription Factors: metabolism
KW  - CBP/p300 (Other)
KW  - Merkel cell carcinoma (Other)
KW  - Merkel cell polyomavirus (Other)
KW  - T antigen (Other)
KW  - cancer reversion (Other)
KW  - E1A-Associated p300 Protein (NLM Chemicals)
KW  - CREB-Binding Protein (NLM Chemicals)
KW  - EP300 protein, human (NLM Chemicals)
KW  - CREBBP protein, human (NLM Chemicals)
KW  - Antigens, Viral, Tumor (NLM Chemicals)
KW  - p300-CBP Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41439710
DO  - DOI:10.1073/pnas.2516667122
UR  - https://inrepo02.dkfz.de/record/307455
ER  -