TY  - JOUR
A1  - Houben, Roland
A1  - Ebert, Marlies
A1  - Hesbacher, Sonja
A1  - Kervarrec, Thibault
A1  - Schrama, David
T1  - Merkel Cell Polyomavirus Large T Antigen is Dispensable in G2 and M-Phase to Promote Proliferation of Merkel Cell Carcinoma Cells
JF  - Viruses
N2  - Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV), and proliferation of MCPyV-positive MCC tumor cells depends on the expression of a virus-encoded truncated Large T antigen (LT) oncoprotein. Here, we asked in which phases of the cell cycle LT activity is required for MCC cell proliferation. Hence, we generated fusion-proteins of MCPyV-LT and parts of geminin (GMMN) or chromatin licensing and DNA replication factor1 (CDT1). This allowed us to ectopically express an LT, which is degraded either in the G1 or G2 phase of the cell cycle, respectively, in MCC cells with inducible T antigen knockdown. We demonstrate that LT expressed only in G1 is capable of rescuing LT knockdown-induced growth suppression while LT expressed in S and G2/M phases fails to support proliferation of MCC cells. These results suggest that the crucial function of LT, which has been demonstrated to be inactivation of the cellular Retinoblastoma protein 1 (RB1) is only required to initiate S phase entry.
KW  - Merkel cell polyomavirus
KW  - large T antigen
KW  - cell cycle
KW  - Merkel cell carcinoma
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218171
SN  - 1999-4915
VL  - 12
IS  - 10
ER  - 
TY  - JOUR
A1  - Orouji, Elias
A1  - Peitsch, Wiebke K.
A1  - Orouji, Azadeh
A1  - Houben, Roland
A1  - Utikal, Jochen
T1  - Oncogenic role of an epigenetic reader of m\(^6\)A RNA modification: YTHDF1 in Merkel cell carcinoma
JF  - Cancers
N2  - Merkel cell carcinoma is a deadly skin cancer, which in the majority of cases is caused by the Merkel cell polyomavirus (MCPyV). The viral small T antigen is regarded as the dominant oncoprotein expressed in the tumor cells. We used genomic screening of copy number aberrations along with transcriptomic analysis to investigate regions with amplification that harbor differentially expressed genes. We identified YTHDF1, a protein that is a reader of N\(^6\)-methyladenosine (m\(^6\)A) RNA modifications, to have high copy gains and to be highly expressed in Merkel cell carcinoma. Importantly, we identified the presence of m\(^6\)A on small T antigen mRNA suggesting a relation between YTHDF1 amplification and MCPyV gene expression. Interestingly, knockdown of YTHDF1 in Merkel cell carcinoma (MCC) cell lines negatively affected the translation initiation factor eIF3 and reduced proliferation and clonogenic capacity in vitro. Furthermore, analysis of survival data revealed worse overall survival in YTHDF1\(^{high}\) MCC patients compared to YTHDF1\(^{low}\) patients. Our findings indicate a novel oncogenic role of YTHDF1 through m\(^6\)A machinery in the tumorigenesis of MCC.
KW  - Merkel cell carcinoma
KW  - Merkel cell polyomavirus
KW  - copy number variations
KW  - m\(^6\)A
KW  - RNA modification
KW  - epitranscriptome
KW  - YTHDF1
KW  - epigenetic reader
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200815
SN  - 2072-6694
VL  - 12
IS  - 1
ER  -