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Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5071-5076. doi: 10.1073/pnas.1815071116. Epub 2019 Feb 27.

OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
2
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195.
3
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
4
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
5
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
6
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
7
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; starkg@ccf.org silverr@ccf.org.

Abstract

Drugs that reverse epigenetic silencing, such as the DNA methyltransferase inhibitor (DNMTi) 5-azacytidine (AZA), have profound effects on transcription and tumor cell survival. AZA is an approved drug for myelodysplastic syndromes and acute myeloid leukemia, and is under investigation for different solid malignant tumors. AZA treatment generates self, double-stranded RNA (dsRNA), transcribed from hypomethylated repetitive elements. Self dsRNA accumulation in DNMTi-treated cells leads to type I IFN production and IFN-stimulated gene expression. Here we report that cell death in response to AZA treatment occurs through the 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway. OASs are IFN-induced enzymes that synthesize the RNase L activator 2-5A in response to dsRNA. Cells deficient in RNase L or OAS1 to 3 are highly resistant to AZA, as are wild-type cells treated with a small-molecule inhibitor of RNase L. A small-molecule inhibitor of c-Jun NH2-terminal kinases (JNKs) also antagonizes RNase L-dependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZA-induced and RNase L-dependent cell death were increased by transfection of 2-5A, by deficiencies in ADAR1 (which edits and destabilizes dsRNA), PDE12 or AKAP7 (which degrade 2-5A), or by ionizing radiation (which induces IFN-dependent signaling). Finally, OAS1 expression correlates with AZA sensitivity in the NCI-60 set of tumor cell lines, suggesting that the level of OAS1 can be a biomarker for predicting AZA sensitivity of tumor cells. These studies may eventually lead to pharmacologic strategies for regulating the antitumor activity and toxicity of AZA and related drugs.

KEYWORDS:

5-azacytidine; DNA methyltransferase inhibitor; OAS; RNase L; innate immunity

PMID:
30814222
PMCID:
PMC6421468
DOI:
10.1073/pnas.1815071116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: S.B. and R.H.S. have a US patent application relating to this study. B.D. and R.H.S. receive royalties for the RNase L antibody used in this study. Y.S. has patents around tetrahydrouridine, decitabine, and 5-azacytidine; and consults for, and has equity and royalty rights with EpiDestiny.

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