Merkel cell polyomavirus pan-T antigen knockdown reduces cancer cell stemness and promotes neural differentiation independent of RB1.
Humans
Merkel cell polyomavirus
/ genetics
Antigens, Viral, Tumor
/ genetics
Cell Line, Tumor
Cell Differentiation
/ genetics
Retinoblastoma Binding Proteins
/ genetics
Gene Knockdown Techniques
Ubiquitin-Protein Ligases
/ genetics
Carcinoma, Merkel Cell
/ virology
Neoplastic Stem Cells
/ virology
Skin Neoplasms
/ virology
Gene Regulatory Networks
Neurons
/ virology
LoKe
T antigens
large T antigen
merkel cell carcinoma
merkel cell polyomavirus
Journal
Journal of medical virology
ISSN: 1096-9071
Titre abrégé: J Med Virol
Pays: United States
ID NLM: 7705876
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
revised:
10
06
2024
received:
29
01
2024
accepted:
02
07
2024
medline:
11
7
2024
pubmed:
11
7
2024
entrez:
11
7
2024
Statut:
ppublish
Résumé
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer associated with integration of Merkel cell polyomavirus (MCPyV). MCPyV-encoded T-antigens (TAs) are pivotal for sustaining MCC's oncogenic phenotype, i.e., repression of TAs results in reactivation of the RB pathway and subsequent cell cycle arrest. However, the MCC cell line LoKe, characterized by a homozygous loss of the RB1 gene, exhibits uninterrupted cell cycle progression after shRNA-mediated TA repression. This unique feature allows an in-depth analysis of the effects of TAs beyond inhibition of the RB pathway, revealing the decrease in expression of stem cell-related genes upon panTA-knockdown. Analysis of gene regulatory networks identified members of the E2F family (E2F1, E2F8, TFDP1) as key transcriptional regulators that maintain stem cell properties in TA-expressing MCC cells. Furthermore, minichromosome maintenance (MCM) genes, which encodes DNA-binding licensing proteins essential for stem cell maintenance, were suppressed upon panTA-knockdown. The decline in stemness occurred simultaneously with neural differentiation, marked by the increased expression of neurogenesis-related genes such as neurexins, BTG2, and MYT1L. This upregulation can be attributed to heightened activity of PBX1 and BPTF, crucial regulators of neurogenesis pathways. The observations in LoKe were confirmed in an additional MCPyV-positive MCC cell line in which RB1 was silenced before panTA-knockdown. Moreover, spatially resolved transcriptomics demonstrated reduced TA expression in situ in a part of a MCC tumor characterized by neural differentiation. In summary, TAs are critical for maintaining stemness of MCC cells and suppressing neural differentiation, irrespective of their impact on the RB-signaling pathway.
Substances chimiques
Antigens, Viral, Tumor
0
Retinoblastoma Binding Proteins
0
RB1 protein, human
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e29789Subventions
Organisme : Bundesministerium für Bildung und Forschung
Organisme : Else Kröner-Fresenius-Stiftung
Informations de copyright
© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.
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