DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts
Open accessAbstract
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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The IFN-I response could expose tumor cells to surveillance by the immune system.
“The IFN-I response could also expose the tumor cells to surveillance by the immune system96, 97.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [96]
The Results section reports that 5-AZA-CdR induced type III, but not type I, interferons in the colorectal cancer cells studied. The Discussion describes tumor-cell immunogenic death through RIG1/MDA5 signaling, but says that antitumor effect appears independent of type I interferon; it does not attribute immune exposure to an IFN-I response. Page numbers are not available in our copy. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDAC treatment could induce expression of retrotransposons normally silenced by DNA methylation, which could augment tumor immunogenicity.
“DAC treatment could induce expression of retrotransposons normally silenced by DNA methylation, which could also augment tumor immunogenicity10–14,99.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [13]
Inactivated typical enhancers in HCC are associated with collagen fibril organization and chemotaxis GO terms and enriched for binding motifs of immune-related TFs, including STAT1.
“inactivated typical enhancers were associated with collagen fibril organization and chemotaxis GO terms and were enriched for binding motifs of immune-related TFs, including STAT1 (Fig. 2a, b)12,13.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [13]
The Results section discusses interferon-responsive signaling and STAT1 in colorectal cancer cell experiments, not inactivated enhancers in HCC. Searches for collagen fibril organization, chemotaxis, and enhancer-binding motifs found no passage addressing those claims in our copy; page numbers were not provided. (LLM, conf=0.75)
Experimental — accuracy not yet measuredIn other tumours, DNA demethylating agents can have the opposite effect.
“For instance, in Hodgkin lymphoma, transcription of the IRF5 transcription factor gene is induced by DNA hypomethylation of a normally dormant endogenous retroviral long terminal repeat located upstream of the promoter, a phenomenon dubbed onco-exaptation 146 , whereas in other tumours, DNA demethylating agents can have the opposite effect 147 .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [147]
Depletion of YTHDF1 enhances cross-presentation of tumour antigens by dendritic cells.
“Depletion of YTHDF1 (YTH N6-methyladenosine binding protein 1), which binds m6A-modified mRNA, enhanced cross-presentation of tumour antigens by dendritic cells.”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [197]
The effect of YTHDF1 depletion was attributed to inhibition of lysosomal protease production and resulted in substantially enhanced CD8+ T-cell mediated anti-tumour immunity in YTHDF1 knockout mice.
“This effect was attributed to inhibition of lysosomal protease production and resulted in substantially enhanced CD8+ T-cell mediated anti-tumour immunity in YTHDF1 knockout mice 197 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [197]
DNMT inhibitors are consistently linked to derepression of endogenous retroviral elements and strong type I and type III interferon signaling.
“derepression of endogenous retroviral elements coupled to robust type I and type III IFN signaling”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Roulois et al., 2015
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Mapping epigenetic modifications by sequencing technologies
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Vitamin C – A new player in regulation of the cancer epigenome
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- Authors
- Roulois, D., Loo Yau, H., Singhania, R., Wang, Y., Danesh, A., Shen, S. Y., Han, H., Liang, G., Jones, P. A., Pugh, T. J., O’Brien, C., & De Carvalho, D. D.
- Affiliations
- University Health Network (CA)
- University of Southern California (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 5
- Pages
- 961-973
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4843502
- OpenAlex
- W1905278501
- Cited by
- 1,527
- References
- 39
- Citations by year
- 2026: 145 · 2025: 148 · 2024: 179 · 2023: 165 · 2022: 162 · 2021: 181 · 2020: 124 · 2019: 124 · 2018: 119 · 2017: 100 · 2016: 72 · 2015: 7
- FWCI
- 42.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA170550, R01CA082422)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- hypomethylating agents, azacitidine, colorectal cancer, cancer stem cells, viral mimicry, endogenous retroviruses, double-stranded RNA, MDA5, MAVS, IRF7, innate antiviral signaling
- MeSH terms
- Interferon-Induced Helicase, IFIH1, Decitabine, Animals, Antimetabolites, Antineoplastic, Azacitidine, Cells, Cultured, Humans, RNA, Double-Stranded, Colorectal Neoplasms, Signal Transduction, Receptors, Retinoic Acid, DNA Methylation, Endogenous Retroviruses, Adaptor Proteins, Signal Transducing, Interferon Regulatory Factor-7, Mice, DEAD-box RNA Helicases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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