TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells
- Roswell Park Cancer Institute, United States
- Buffalo BioLabs, United States
- Ariel University, Israel
- Blokhin Cancer Research Center, Russian Federation
Abstract
Cellular Responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anti-cancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.
Data availability
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Effect of CBL0137 on gene expression in mouse cells and tissuesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE102768).
Article and author information
Author details
Funding
National Cancer Institute (RO1CA197967)
- Katerina Gurova
National Cancer Institute (R21CA198395)
- Katerina Gurova
Russian Science Foundation (17-15-01526)
- Marianna G Yakubovskaya
Roswell Park Cancer Center (P30CA016056)
- Katerina Gurova
Incuron LLC
- Katerina Gurova
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#1093M) of Roswell Park Cancer Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments of Roswell Park Cancer Institute.
Copyright
© 2018, Leonova et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells
eLife 7:e30842.
https://doi.org/10.7554/eLife.30842
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