Journal
CELL
Volume 162, Issue 5, Pages 961-973Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.07.056
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Funding
- Cancer Research Society [CRS19092, CRS19091]
- Canadian Cancer Society [CCSRI 703279, CCSRI 703716]
- NSERC [489073]
- Ontario Institute for Cancer Research (OICR)
- province of Ontario
- Princess Margaret Cancer Foundation
- University of Toronto McLaughlin Centre [MC-2015-02]
- NCI [5R01CA082422]
- Stand Up to Cancer
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DNA-demethylating agents have shown clinical antitumor 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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