DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts
By David Roulois, H. Yau, Rajat Singhania, Yadong Wang, A. Danesh, S. Y. Shen, Han F Han, G. Liang, Peter A. Jones, Trevor J Pugh and 2 more. Cell, 2015
1,340 citations recorded by the source corpus.
Summary DNA demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analysis 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 antitumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs.
Subfields: Cancer Research, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/535d7d55e244e9ad5d6c6ec81fe807381e1441c9
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Citations in the corpus
- DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity (2020, background): “Accumulating evidence indicates that during cellular stress conditions, endogenous RNA transcripts can be sensed by host PRRs and trigger inflammation (Tarallo et al. 2012; Boelens et al. 2014; White et al. 2014; Chiappinelli et al. 2015; Liddicoat et al. 2015; Roulois et al. 2015; Nabet et al. 2017”
- DE NOVO EPIGENETIC PROGRAMS INHIBIT PD-1 BLOCKADE-MEDIATED T-CELL REJUVENATION (2017, positive): “In addition to exploiting natural mechanisms of epigenetic reversal, it may be possible to directly reverse epigenetic modifications with existing chemotherapeutics (Chiappinelli et al., 2016; Roulois et al., 2015; Wang et al., 2015).”
- Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “Hypomethylating agents (e.g., 5-aza cytidine) can induce innate immune responses (Roulois et al, 2015), influence T-cell priming and effector function, modulate immune suppressive cells within the TME (Kim et al, 2014), and enhance response to ICI through induction of endogenous retroviral elements…”