Abstract
Merkel cell carcinoma (MCC) is a deadly skin cancer, and about 80% of its cases have been shown to harbor integrated Merkel polyomavirus in the tumor cell genome. Viral oncoproteins expressed in the tumor cells are considered as the oncogenic factors of these virus-positive Merkel cell carcinoma (VP-MCC). In contrast, the molecular pathogenesis of virus-negative MCC (VN-MCC) is less well understood. Using gene expression analysis of MCC cell lines, we found histone methyltransferase PRDM8 to be elevated in VN-MCC. This finding was confirmed by immunohistochemical analysis of MCC tumors, revealing that increased PRDM8 expression in VN-MCC is also associated with increased H3K9 methylation. CRISPR-mediated silencing of PRDM8 in MCC cells further supported the histone methylating role of this protein in VN-MCC. We also identified miR-20a-5p as a negative regulator of PRDM8. Taken together, our findings provide insights into the role of PRDM8 as a histone methyltransferase in VN-MCC tumorigenesis.
Highlights
Merkel cell carcinoma (MCC) is a lethal skin cancer, frequently associated with the Merkel cell polyomavirus (MCV), which is found clonally integrated in about 80% of cases [1,2]
Because H3K9me3 is considered as a histone mark that is widely associated with transcriptional repression, higher levels of this histone modification could have a global impact on the transcription machinery and can potentially repress gene transcription in a number of genes, which can lead to the unique characteristics of virus-negative MCC (VN-MCC) tumors that are known to be quite different from that of virus-positive Merkel cell carcinoma (VP-MCC) tumors [26,27]
Our findings in this study showed that silencing PRDM8 either through sgRNA-clustered regularly interspaced short palindromic repeats (CRISPR) knockout of the gene or miR-20a-5p overexpression could lead to global changes in heterochromatin pattern in VN-MCC cells, and that this could further reduce the tumorigenic capacity of the cells
Summary
Merkel cell carcinoma (MCC) is a lethal skin cancer, frequently associated with the Merkel cell polyomavirus (MCV), which is found clonally integrated in about 80% of cases [1,2]. There is little understanding about the underlying tumorigenesis mechanisms of virus-negative MCC (VN-MCC). Epidemiological data support clinically relevant differences between the two subtypes [6], suggesting even different cells of origin for them. Integration of MCV genome into the host cells and accidental fragmentation of the genome during this process, leading to the oncogenic transformation by MCV, is the proposed mechanism of tumorigenesis in VP-MCC. No particular host for the virus has been identified in VP-MCCs, there are studies suggesting blood monocytes as a route of dissemination of MCV in the human body
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