Format

Send to

Choose Destination
J Invest Dermatol. 2019 Jul 5. pii: S0022-202X(19)31853-6. doi: 10.1016/j.jid.2019.06.135. [Epub ahead of print]

MCPyV Large T antigen induced atonal homolog 1 (ATOH1) is a lineage-dependency oncogene in Merkel cell carcinoma.

Author information

1
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Medical University of Graz, Graz, Austria.
2
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Department of Medical Biology, University of Tromsø, Tromsø, Norway.
4
Department of Dermatology, Ruhr-Universität Bochum, Bochum, Germany.
5
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, United States.
6
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
7
Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address: j.becker@dkfz.de.

Abstract

Despite the fact that the transcription factor atonal homolog 1 (ATOH1) is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependency oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, i.e. one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension/ spheroidal growth, i.e., resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV) derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphologic changes. In summary, MCPyV associated carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependency oncogene in MCC.

KEYWORDS:

ATOH1; LT; MCPyV; Neuroendocrine; miR-375

PMID:
31283928
DOI:
10.1016/j.jid.2019.06.135

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center