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Cell. 2015 Aug 27;162(5):961-73. doi: 10.1016/j.cell.2015.07.056.

DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
3
Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Surgery, Toronto General Hospital, Toronto, ON M5T 1P5, Canada.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada. Electronic address: ddecarv@uhnres.utoronto.ca.

Abstract

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.

PMID:
26317465
PMCID:
PMC4843502
DOI:
10.1016/j.cell.2015.07.056
[Indexed for MEDLINE]
Free PMC Article

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