Orouji Elias, Peitsch Wiebke K, Orouji Azadeh, Houben Roland, Utikal Jochen
Skin Cancer Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Cancers (Basel). 2020 Jan 14;12(1):202. doi: 10.3390/cancers12010202.
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-methyladenosine (mA) RNA modifications, to have high copy gains and to be highly expressed in Merkel cell carcinoma. Importantly, we identified the presence of mA 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 MCC patients compared to YTHDF1 patients. Our findings indicate a novel oncogenic role of YTHDF1 through mA machinery in the tumorigenesis of MCC.
默克尔细胞癌是一种致命的皮肤癌，在大多数情况下由默克尔细胞多瘤病毒（MCPyV）引起。病毒小T抗原被认为是肿瘤细胞中表达的主要致癌蛋白。我们使用拷贝数变异的基因组筛选以及转录组分析来研究含有差异表达基因的扩增区域。我们鉴定出YTHDF1，一种作为N-甲基腺苷（mA）RNA修饰识别蛋白的蛋白质，在默克尔细胞癌中具有高拷贝增益且高表达。重要的是，我们在小T抗原mRNA上鉴定出了mA 的存在，这表明YTHDF1扩增与MCPyV基因表达之间存在关联。有趣的是，在默克尔细胞癌（MCC）细胞系中敲低YTHDF1会对翻译起始因子eIF3产生负面影响，并降低体外增殖和克隆形成能力。此外，生存数据分析显示，与YTHDF1阴性的患者相比，YTHDF1阳性的MCC患者总生存期更差。我们的研究结果表明，YTHDF1通过mA机制在MCC的肿瘤发生中具有新的致癌作用。
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