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.

Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases

“…DNA methylation occurs mainly on CpG islands in gene promoter regions [54,55]. The enzymes that catalyze DNA methylation are the DNA methyltransferases (DNMTs), including DNMT1, DNMT2, and DNMT3 [56,57]. Demethylation is the reverse process of methylation in which a methyl group is removed [58,59].…”

“…Histones H1, H2A, H2B, H3, and H4 are small nuclear proteins rich in positively charged basic amino acids, i.e., arginine and lysine, which can interact with the negatively charged DNA [56]. The interaction between an octamer of four histones (H2A/2B/3/4) and a 147-bp segment of DNA leads to chromatin compaction and assembly into the nucleosome, which is the basic chromatin unit [56]. The continuous nucleosome formation and folding are at the bases of the chromatin remodeling processes that regulate gene expression.…”

“…PTMs modulate the expression of genes, ultimately leading to the regulation of a large variety of cell functions, including osteogenesis [81,90,91]. The main histone modifications comprise (de)acetylation, (de)methylation, (de)phosphorylation, and ubiquitylation modifications [56]. Histones PTMs are modulated by several classes of modifying enzymes, including (i) histone acetyltransferases (HATs) and histone deacetylases (HDACs); (ii) histone methyltransferases and demethylases, and (iii) histone kinases and phosphatases, that promote or eradicate specific modifications, respectively [56].…”

“…miRNAs are small RNA transcripts consisting of ∼22 nucleotides that regulate gene expression by binding 3 -UTR of mRNA targets [113]. The complete complementarity of miRNAs with the mRNA target induces its degradation [56], while miRNA-mRNA incomplete binding leads to mRNA expression inhibition [114]. Several studies demonstrated miRNA involvement in the epigenetic regulation of bone remodeling.…”

Functional Domains of the Early Proteins and Experimental and Epidemiological Studies Suggest a Role for the Novel Human Polyomaviruses in Cancer

“…SV40, BKPyV, JCPyV and MCPyV were found to provoke epigenetic changes (Balakrishnan and Milavetz, 2017;Pietropaolo et al, 2021). Epigenetic dysregulation seems to be a driving mechanism in MCPyV-positive MCC, with altered DNA methylation, histone and chromatin modifications, and microRNA regulation (Pietropaolo et al, 2021;Rotondo et al, 2021). Little is known about the effect of the nHPyVs on epigenetic changes in infected cells.…”