Epigenetic Dysregulations in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma

Abstract

Merkel cell polyomavirus (MCPyV) is a small DNA virus with oncogenic potential. MCPyV is the causative agent of Merkel Cell Carcinoma (MCC), a rare but aggressive tumor of the skin. The role of epigenetic mechanisms, such as histone posttranslational modifications (HPTMs), DNA methylation, and microRNA (miRNA) regulation on MCPyV-driven MCC has recently been highlighted. In this review, we aim to describe and discuss the latest insights into HPTMs, DNA methylation, and miRNA regulation, as well as their regulative factors in the context of MCPyV-driven MCC, to provide an overview of current findings on how MCPyV is involved in the dysregulation of these epigenetic processes. The current state of the art is also described as far as potentially using epigenetic dysregulations and related factors as diagnostic and prognostic tools is concerned, in addition to targets for MCPyV-driven MCC therapy. Growing evidence suggests that the dysregulation of HPTMs, DNA methylation, and miRNA pathways plays a role in MCPyV-driven MCC etiopathogenesis, which, therefore, may potentially be clinically significant for this deadly tumor. A deeper understanding of these mechanisms and related factors may improve diagnosis, prognosis, and therapy for MCPyV-driven MCC.

Keywords: DNA methylation; HPTMs; Merkel cell carcinoma (MCC); Merkel cell polyomavirus (MCPyV); epigenetics; histone posttranslational modifications; miRNA; microRNA; virus-driven tumors.

Figure 1

Epigenetic mechanisms. Epigenetic mechanisms comprise (A) histone posttranslational modifications (HPTMs), (B) DNA methylation, and (C) microRNAs (miRNAs) regulation. Gene expression can be regulated before transcription initiation by HPTMs and DNA methylation. Both mechanisms induce a remodeling of the chromatin structure, thereby making genes either less or more accessible for transcription factors, according to the different epigenetic modifications. Unlike DNA methylation and HPTMs, miRNAs regulate the expression of genes at the post-transcriptional level. miRNAs negatively regulate genes through complementing their mRNAs, which results in mRNA degradation or translational repression.

Figure 2

Impairment of epigenetic mechanisms in Merkel cell polyomavirus (MCPyV)-driven Merkel cell carcinoma. MCPyV sT promotes LSD1 expression through histone acetylation activation to induce cellular transformation. MCPyV sT can induce H2AX phosphorylation and H3K4 and H4K20 dimethylation (H3K4me2 and H4K20me2), thereby leading to the DNA damage response pathway activation. Tumor suppressor genes silencing via H3K27me3 mark might be a mechanism in MCPyV-driven MCC tumorigenesis. Loss of HLA class-I and MICA/B expression via H3K9 deacetylation might represent a strategy to evade the antiviral/-tumoral immune response. MCPyV LT/sT expression can upregulate miRNAs targeting genes involved in autophagy/cell death, such as ATG7, SQSTM1/p62, and BECN1. Continuous arrows—epigenetic dysregulation determined functionally in vitro. Dashed arrows—hypothesized epigenetic mechanisms. LT/sT (?)—the role of MCPyV LT/sT proteins has not been demonstrated.