Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States; Department of Molecular Biology, Ariel University, Ariel, Israel
Poorva Sandlesh
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
Rachel Pratt
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
Catherine Burkhart
Buffalo BioLabs, Buffalo, United States
Brittany Lipchick
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
Ilya Gitlin
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
Costakis Frangou
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
Igor Koman
Department of Molecular Biology, Ariel University, Ariel, Israel
Jianmin Wang
Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States
Kirill Kirsanov
Department of Chemical Carcinogenesis, Institute of Carcinogenesis, Blokhin Cancer Research Center RAMS, Moscow, Russia
Marianna G Yakubovskaya
Department of Chemical Carcinogenesis, Institute of Carcinogenesis, Blokhin Cancer Research Center RAMS, Moscow, Russia
Andrei V Gudkov
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States
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 anticancer 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.