Cell
Volume 162, Issue 5, 27 August 2015, Pages 961-973
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Article
DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts

https://doi.org/10.1016/j.cell.2015.07.056Get rights and content
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Highlights

  • 5-AZA-CdR induces formation of dsRNAs and activation of the MDA5/MAVS/IRF7 pathway

  • An anti-proliferative response to DNA demethylation is mediated by viral mimicry

  • 5-AZA-CdR-mediated targeting of CICs is mainly mediated by viral mimicry

  • The MDA5/MAVS/IRF7 pathway is a potentially druggable target against colorectal cancer

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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Present address: Van Andel Research Institute, Grand Rapids, MI 49503, USA