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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Cells, Cultured
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / immunology*
  • DEAD-box RNA Helicases / metabolism
  • DNA Methylation / drug effects
  • Decitabine
  • Endogenous Retroviruses / metabolism
  • Humans
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-Induced Helicase, IFIH1
  • Mice
  • RNA, Double-Stranded / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • Antimetabolites, Antineoplastic
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • MAVS protein, human
  • PLAAT4 protein, human
  • RNA, Double-Stranded
  • Receptors, Retinoic Acid
  • Decitabine
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • Azacitidine

Associated data

  • GEO/GSE62086