[HTML][HTML] DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts

D Roulois, HL Yau, R Singhania, Y Wang, A Danesh… - Cell, 2015 - cell.com
D Roulois, HL Yau, R Singhania, Y Wang, A Danesh, SY Shen, H Han, G Liang, PA Jones
Cell, 2015cell.com
DNA-demethylating agents have shown clinical anti-tumor efficacy via an unknown
mechanism of action. Using a combination of experimental and bioinformatics analyses in
colorectal cancer cells, we demonstrate that low-dose 5-AZA-CdR targets colorectal cancer-
initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs
derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS
RNA recognition pathway, and downstream activation of IRF7. Indeed, disruption of virus …
Summary
DNA-demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analyses in colorectal cancer cells, we demonstrate that low-dose 5-AZA-CdR targets colorectal cancer-initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS RNA recognition pathway, and downstream activation of IRF7. Indeed, disruption of virus recognition pathways, by individually knocking down MDA5, MAVS, or IRF7, inhibits the ability of 5-AZA-CdR to target colorectal CICs and significantly decreases 5-AZA-CdR long-term growth effects. Moreover, transfection of dsRNA into CICs can mimic the effects of 5-AZA-CdR. Together, our results represent a major shift in understanding the anti-tumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs.
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