Home > Publications database > Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition. > print

001     307455
005     20260304121006.0
024 7 _ |a 10.1073/pnas.2516667122
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024 7 _ |a 0027-8424
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024 7 _ |a 1091-6490
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037 _ _ |a DKFZ-2025-03054
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Collura, Joseph L
|b 0
245 _ _ |a Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition.
260 _ _ |a Washington, DC
|c 2025
|b National Acad. of Sciences
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a CBP/p300
|2 Other
650 _ 7 |a Merkel cell carcinoma
|2 Other
650 _ 7 |a Merkel cell polyomavirus
|2 Other
650 _ 7 |a T antigen
|2 Other
650 _ 7 |a cancer reversion
|2 Other
650 _ 7 |a E1A-Associated p300 Protein
|0 EC 2.3.1.48
|2 NLM Chemicals
650 _ 7 |a CREB-Binding Protein
|0 EC 2.3.1.48
|2 NLM Chemicals
650 _ 7 |a EP300 protein, human
|0 EC 2.3.1.48
|2 NLM Chemicals
650 _ 7 |a CREBBP protein, human
|0 EC 2.3.1.48
|2 NLM Chemicals
650 _ 7 |a Antigens, Viral, Tumor
|2 NLM Chemicals
650 _ 7 |a p300-CBP Transcription Factors
|0 EC 2.3.1.48
|2 NLM Chemicals
650 _ 2 |a Carcinoma, Merkel Cell: drug therapy
|2 MeSH
650 _ 2 |a Carcinoma, Merkel Cell: metabolism
|2 MeSH
650 _ 2 |a Carcinoma, Merkel Cell: pathology
|2 MeSH
650 _ 2 |a Carcinoma, Merkel Cell: genetics
|2 MeSH
650 _ 2 |a Carcinoma, Merkel Cell: virology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Merkel cell polyomavirus: metabolism
|2 MeSH
650 _ 2 |a E1A-Associated p300 Protein: antagonists & inhibitors
|2 MeSH
650 _ 2 |a E1A-Associated p300 Protein: metabolism
|2 MeSH
650 _ 2 |a CREB-Binding Protein: antagonists & inhibitors
|2 MeSH
650 _ 2 |a CREB-Binding Protein: metabolism
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Gene Expression Regulation, Neoplastic: drug effects
|2 MeSH
650 _ 2 |a Skin Neoplasms: drug therapy
|2 MeSH
650 _ 2 |a Skin Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Skin Neoplasms: pathology
|2 MeSH
650 _ 2 |a Skin Neoplasms: genetics
|2 MeSH
650 _ 2 |a Antigens, Viral, Tumor: metabolism
|2 MeSH
650 _ 2 |a Antigens, Viral, Tumor: genetics
|2 MeSH
650 _ 2 |a Cell Proliferation: drug effects
|2 MeSH
650 _ 2 |a Cell Differentiation: drug effects
|2 MeSH
650 _ 2 |a p300-CBP Transcription Factors: antagonists & inhibitors
|2 MeSH
650 _ 2 |a p300-CBP Transcription Factors: metabolism
|2 MeSH
700 1 _ |a Lei, Kuan Cheok
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700 1 _ |a Chandra, Mitalee
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700 1 _ |a Kervarrec, Thibault
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700 1 _ |a Park, Hyun Jung
|0 0000-0002-8324-2624
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700 1 _ |a Dalkoohi, Mazdak
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700 1 _ |a Becker, Jürgen
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700 1 _ |a Chang, Yuan
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700 1 _ |a Moore, Patrick S
|0 0000-0002-8132-858X
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700 1 _ |a Shuda, Masahiro
|0 0000-0003-0595-2572
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773 _ _ |a 10.1073/pnas.2516667122
|g Vol. 122, no. 52, p. e2516667122
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