Epigenetic Mechanisms in Canine Cancer

Abstract

A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

“…An addition level of complexity is added through the dynamics of the epigenome, with gene expression regulated by a variety of reversible modifications of DNA or histones, and translation of mRNA influenced by a diverse array of non-coding RNAs [65]. One such epigenetic mark is DNA methylation of cytosine residues in CpG dinucleotides.…”

“…These sites are found in repetitive elements throughout the genome, and clustered in so-called CpG islands (CGI), which are present in the promotor regions of around half of all mammalian genes [66]. While the former are usually methylated, CGIs are frequently unmethylated, and within promoters, methylation can lead to gene silencing, either through a steric interference with transcription machinery, or by recruiting chromatin remodelling factors [65]. A recent canine study has taken an IHC approach with a monoclonal antibody to 5-methylcytosine, revealing predominantly weak staining or negative nuclei in COMs, but staining intensity in normal melanocytes was not determined, and gene-specific methylation was not determined [67].…”

An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology

“…LncRNAs are non-coding transcripts >than 200 bp in length, and different studies demonstrated the influence of these molecules in gene expression at the epigenetic, transcriptional, and post-transcriptional levels. One of the most classical mechanisms through which lncRNAs regulate gene expression involves their association with chromatin modeling complexes and transcription factors, influencing transcriptional repression and activation of gene promoters ( 211 ).…”

“…Among the multiple epigenetic mechanisms found in canine cancer, DNA methylation and histone modification have been identified on the basis of OSA progression ( 211 ). Le Beguec et al characterized the expression profiles of 10.444 canine lncRNAs in 26 distinct tissue types.…”

“…Other studies observed more than 900 dog-human conserved lncRNAs using comparative genomics, confirming the presence of well-studied lncRNAs in dogs, such as HOTAIR and MALAT 1 in canine B cell lymphoma and identifying lncRNAs differential expression as a prognostic tool (218)(219)(220). Of relevance, 417 differentially expressed lncRNAs were identified in canine oral melanomas in comparison with control samples, including the well-studied lncRNA ZEB2-AS, a lncRNA involved in the regulation of the transcription factor Zinc Finger E-Box Binding Homeobox 2 (Zeb2) during EMT in human colon, pancreatic, and breast cancer cell lines, as well as SOX21 Antisense Divergent Transcript 1(Sox21-as1) and Cancer Susceptibility 15(Casc15) (211,221,222). Finally, long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity in canine tumor cell lines originated from soft tissue sarcomas (223).…”