Figure 2.

Transposable elements determine the inherent immunogenicity and response of tumor cells to epigenetic agents. Transposable elements (TE) in the genome are typically not actively transcribed but can be stimulated by stress and epigenetic agents. Endogenous retroviruses (ERVs) compose a major part of TE. Regionally hypermethylated ERVs are transcriptionally inactive, and repressive histone modifications at ERVs loci disturb the access of genome for transcription factors (TF). Epigenetic agents potentiate the transcription of ERVs into nucleic acids that mimic a virus infection. The transcription product of ERVs, dsRNA, are sensed by cytosolic sensors: retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5). The resulting signal is transduced by mitochondrial antiviral proteins (MAVs) and leads to NF-kb and interferon regulated factors (IRF) translocation into the nucleus, inducing the expression of interferon-stimulated genes (ISGs) and type I IFN response and results in tumor cell apoptosis or enhanced expression of tumor associated antigens. Hypomethylated ERVs may be a characteristic epigenetic feature in tumor cells and may perturb cellular responses to epigenetic agents. Inherent ERV patterns and regional epigenetic modifications may provide predictive value for epigenetic therapy [52,100,101].