Fig. 3

ERVs contribute to oncogenesis and may be targeted therapeutically. a Onco-exapted ERVs can regulate host gene expression in tumors. Hypomethylated ERV LTRs can be bound by transcription factors (TF) and serve as alternative promoters to induce the expression of oncogenes contributing to oncogenesis (top). They may also be decorated with H3K27ac and H3K4me1 (light green) and act as enhancers to drive the expression of adjacent or distal genes (bottom). Note: empty white circles represent unmethylated CpG dinucleotides. b HERV proteins, such as Env, can be expressed from intact HERV provirus ORFs in cancer cells (left). In breast and endometrial carcinoma models, Env has been detected on the cell membrane and is able to mediate cellular fusion with endothelial cells [154, 155] (middle). Env can promote tumorigenesis, for example by stimulating the RAS/RAF/MEK/ERK pathway in breast cancer models [156]. c Proposed model for therapeutic targeting of ERV-induced viral mimicry to promote immune detection of tumor cells. ERV reactivation can be induced by a number of therapeutic agents that target chromatin modifying enzymes (blue box). Derepression of ERV LTRs results in the production of dsRNA molecules, which can be detected by cytosolic dsRNA sensors TLR3 and MDA5 [101, 102, 134]. MDA5 binds to MAVS in the mitochondria and stimulates a signalling cascade which promotes the phosphorylation, dimerisation, and nuclear translocation of interferon regulatory factors (IRFs). IRFs drive a type I/III interferon response to spur cytokine production and increase the immunogenicity of the cell. Viral mimicry synergises with production and presentation of ERV-derived tumor associated antigens (green dot) via MHC-I, to increase the visibility of tumor cells for immunogenic death by cytolytic T cell activation