title: DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.
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.
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors: David
authors: D
authors: Roulois
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors: Helen
authors: H
authors: Loo Yau
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors: Rajat
authors: R
authors: Singhania
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors: Yadong
authors: Y
authors: Wang
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors: Arnavaz
authors: A
authors: Danesh
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
authors: Shu Yi
authors: SY
authors: Shen
authors: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Han
authors: H
authors: Han
authors: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Gangning
authors: G
authors: Liang
authors: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Peter A
authors: PA
authors: Jones
authors: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors: Trevor J
authors: TJ
authors: Pugh
authors: 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.
authors: Catherine
authors: C
authors: O'Brien
authors: 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.
authors: Daniel D
authors: DD
authors: De Carvalho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D020077:Endogenous Retroviruses / Q000378:metabolism; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D012330:RNA, Double-Stranded / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C505371:MAVS protein, human; C437968:PLAAT4 protein, human; D012330:RNA, Double-Stranded; D018168:Receptors, Retinoic Acid; D000077209:Decitabine; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D001374:Azacitidine