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000307455 0247_ $$2ISSN$$a1091-6490
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000307455 1001_ $$aCollura, Joseph L$$b0
000307455 245__ $$aPharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition.
000307455 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2025
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000307455 520__ $$aMerkel cell polyomavirus (MCV) T antigen functions as an oncoprotein that drives the transformation of Merkel cell carcinoma (MCC) cells by activating transcription factors involved in cell proliferation. The viral T antigen promoter requires the activity of the cellular coactivator CREB-binding protein (CBP)/p300 for its expression. Inhibition of CBP/p300 with two distinct small-molecule inhibitors suppresses T antigen expression, leading to cell cycle arrest and upregulation of the cell cycle inhibitor p27Kip1. This shift promotes neuronal differentiation, associated with neurite outgrowth in MCC cells. RNA sequencing revealed downregulation of genes involved in E2F, Myc, mTORC1 oncogenic signaling, as well as markers of the Merkel cell lineage including Sox2 and Atoh1. Notably, a rare MCC case exhibiting a mixed cellular composition, with loss of T antigen expression and neuroblastic phenotype, showed a transcriptomic profile resembling that of MCC cells treated with CBP/p300 inhibitors. This suggests that similar differentiation processes may contribute to tumor heterogeneity in patients. This study presents the model system enabling reversible switching between a transformed and differentiated cell state in a human cancer using small-molecule treatment.
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000307455 650_7 $$2Other$$aCBP/p300
000307455 650_7 $$2Other$$aMerkel cell carcinoma
000307455 650_7 $$2Other$$aMerkel cell polyomavirus
000307455 650_7 $$2Other$$aT antigen
000307455 650_7 $$2Other$$acancer reversion
000307455 650_7 $$0EC 2.3.1.48$$2NLM Chemicals$$aE1A-Associated p300 Protein
000307455 650_7 $$0EC 2.3.1.48$$2NLM Chemicals$$aCREB-Binding Protein
000307455 650_7 $$0EC 2.3.1.48$$2NLM Chemicals$$aEP300 protein, human
000307455 650_7 $$0EC 2.3.1.48$$2NLM Chemicals$$aCREBBP protein, human
000307455 650_7 $$2NLM Chemicals$$aAntigens, Viral, Tumor
000307455 650_7 $$0EC 2.3.1.48$$2NLM Chemicals$$ap300-CBP Transcription Factors
000307455 650_2 $$2MeSH$$aCarcinoma, Merkel Cell: drug therapy
000307455 650_2 $$2MeSH$$aCarcinoma, Merkel Cell: metabolism
000307455 650_2 $$2MeSH$$aCarcinoma, Merkel Cell: pathology
000307455 650_2 $$2MeSH$$aCarcinoma, Merkel Cell: genetics
000307455 650_2 $$2MeSH$$aCarcinoma, Merkel Cell: virology
000307455 650_2 $$2MeSH$$aHumans
000307455 650_2 $$2MeSH$$aMerkel cell polyomavirus: metabolism
000307455 650_2 $$2MeSH$$aE1A-Associated p300 Protein: antagonists & inhibitors
000307455 650_2 $$2MeSH$$aE1A-Associated p300 Protein: metabolism
000307455 650_2 $$2MeSH$$aCREB-Binding Protein: antagonists & inhibitors
000307455 650_2 $$2MeSH$$aCREB-Binding Protein: metabolism
000307455 650_2 $$2MeSH$$aCell Line, Tumor
000307455 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic: drug effects
000307455 650_2 $$2MeSH$$aSkin Neoplasms: drug therapy
000307455 650_2 $$2MeSH$$aSkin Neoplasms: metabolism
000307455 650_2 $$2MeSH$$aSkin Neoplasms: pathology
000307455 650_2 $$2MeSH$$aSkin Neoplasms: genetics
000307455 650_2 $$2MeSH$$aAntigens, Viral, Tumor: metabolism
000307455 650_2 $$2MeSH$$aAntigens, Viral, Tumor: genetics
000307455 650_2 $$2MeSH$$aCell Proliferation: drug effects
000307455 650_2 $$2MeSH$$aCell Differentiation: drug effects
000307455 650_2 $$2MeSH$$ap300-CBP Transcription Factors: antagonists & inhibitors
000307455 650_2 $$2MeSH$$ap300-CBP Transcription Factors: metabolism
000307455 7001_ $$0P:(DE-He78)35d8806a997d1a0e9d661e88e4979d0e$$aLei, Kuan Cheok$$b1$$udkfz
000307455 7001_ $$aChandra, Mitalee$$b2
000307455 7001_ $$00000-0002-2201-6914$$aKervarrec, Thibault$$b3
000307455 7001_ $$00000-0002-8324-2624$$aPark, Hyun Jung$$b4
000307455 7001_ $$aDalkoohi, Mazdak$$b5
000307455 7001_ $$0P:(DE-He78)7bf2f090fe39a6cd6f0bccf5ea2d4fb3$$aBecker, Jürgen$$b6$$udkfz
000307455 7001_ $$00000-0003-1125-4041$$aChang, Yuan$$b7
000307455 7001_ $$00000-0002-8132-858X$$aMoore, Patrick S$$b8
000307455 7001_ $$00000-0003-0595-2572$$aShuda, Masahiro$$b9
000307455 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2516667122$$gVol. 122, no. 52, p. e2516667122$$n52$$pe2516667122$$tProceedings of the National Academy of Sciences of the United States of America$$v122$$x0027-8424$$y2025
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