Figure 3.

DNMTs inhibitors activate the expression of endogenous retroviruses in cancer cells. Treatment with DNMTs inhibitors (blue arrow) causes loss of DNA methylation in the long terminal repeats (LTR) of endogenous retroviruses (ERVs) and activation of bidirectional transcription, which leads to the formation of double-stranded RNA (dsRNA). dsRNA are sensed in the cytoplasm by cytosolic receptors MDA5/RIG-I/LTRs that initiate signaling cascades to mediate the phosphorylation of interferon responsive factors (IRFs) that, in turn, activate the expression of target genes in the nucleus, including IFNs. INFs activate JAK/STAT-dependent signaling pathways, which result in the induction of interferon stimulated genes (ISGs).