TRAIN in response to treatment with anti-cancer small molecule destabilizing chromatin

Leonova, Y.; Safina, A.; Nesher, E.; Sandlesh, P.; Pratt, R.; Burkhart, C.; Lipchick, B.; Frangou, C.; Koman, I.; Wang, J.; Kirsanov, K.; Yakubovskaya, M.; Gudkov, A.; Gurova, K.

doi:10.1101/142471

bioRxiv · 10.1101/142471

TRAIN in response to treatment with anti-cancer small molecule destabilizing chromatin

Leonova, Y.·Safina, A.·Nesher, E.·Sandlesh, P.·Pratt, R.·Burkhart, C.·Lipchick, B.·Frangou, C.·Koman, I.·Wang, J.·Kirsanov, K.·Yakubovskaya, M.·Gudkov, A.·Gurova, K.

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Abstract

The anticancer activity of genotoxic agents has been intensively studied, while the mechanisms of action of drugs destabilizing the epigenome are far less understood. We previously found that DNA hypomethylation in the absence of p53 leads to transcriptional desilencing of repetitive DNA elements, such as pericentromeric repeats and endogenous retroelements, which is associated with an interferon type I response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, a small molecule anticancer drug candidate, which destabilizes nucleosomes via disruption of histone/DNA interactions, can induce TRAIN independently of the p53 status of a cell. Furthermore, curaxin inhibits oncogene-induced transformation in an interferon-dependent manner, suggesting that cancer prevention by curaxin, previously attributed to its p53-activating and NF-kappaB-inhibiting activities, may also involve the induction of the interferon response to epigenetic derepression of the cellular \"repeatome.\" Moreover, we observed that another type of drugs decondensing chromatin, histone deacetylase inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of cells via elimination of cells with desilenced chromatin.

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Leonova, Y., Safina, A., Nesher, E., Sandlesh, P., Pratt, R., Burkhart, C., Lipchick, B., Frangou, C., Koman, I., Wang, J., Kirsanov, K., Yakubovskaya, M., Gudkov, A., Gurova, K.. 2017-05-26. TRAIN in response to treatment with anti-cancer small molecule destabilizing chromatin. https://doi.org/10.1101/142471

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