The Role of Viral Mimicry in Colitis-Associated Cancer
Abstract
Almost half of the human genome is comprised of transposable elements (TEs), that are endogenous viral elements in the DNA. In homeostasis, these elements are repressed by multiple mechanisms including epigenetic mechanisms such as DNA methylation and binding of the negative regulator tumor protein 53 (TP53). Interestingly, it was recently shown that re-expression of these elements inhibits tumor growth by activation of an interferon response also known as a viral mimicry response. The role that viral mimicry plays during colitis and cancer initiation, however, is not well understood. Here, we examined the role of viral mimicry on colitis-associated cancer initiation. Our findings demonstrate that re-expression of transposable elements and activation of a viral mimicry response (by inhibition of DNA methylation or p53 loss) inhibits colitis-associated cancer initiation. Importantly, loss of viral mimicry by knockout of the anti-viral signaling protein, mitochondrial antiviral-signaling protein (MAVS), reversed the antitumor effect of DNA hypomethylation and p53 loss and further promoted tumor formation. Furthermore, we found that activation of the viral mimicry response by DNA hypomethylation or p53 loss inhibits cancer initiation in a cell-autonomous manner with knockout of MAVS reversing this effect. Finally, we demonstrate that active colitis in both mice and patients is associated with activation of a viral mimicry response that is downregulated during early cancer development (i.e. dysplasia). These findings are consistent with viral mimicry playing a tumor suppressive role in colitis-associated tumorigenesis. Thus, our findings demonstrate that transposable elements and the viral mimicry response play an important role in colitis and colitis-associated cancer.