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

Shuvojit Banerjee, Elona Gusho, Christina Gaughan, Beihua Dong, Xiaorong Gu, Elise Holvey-Bates, Manisha Talukdar, Yize Li, Susan R. Weiss, Frank Sicheri, Yogen Saunthararajah, George R. Stark, Robert H. Silverman

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 NH 2 -terminal kinases (JNKs) also antagonizes RNase Ldependent cell death in response to AZA, consistent with a role for JNK in RNase L-induced apoptosis. In contrast, the rates of AZAinduced 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.

Original languageEnglish (US)
Pages (from-to)5071-5076
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number11
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • 5-azacytidine
  • DNA methyltransferase inhibitor
  • Innate immunity
  • OAS
  • RNase L

ASJC Scopus subject areas

  • General

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