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

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.

Identification of a prognostic gene signature based on an immunogenomic landscape analysis of bladder cancer

“…OAS1 is an antiviral protein (AVP) induced by interferon, and it plays an important role in antiviral immunity by regulating multiple signalling pathways 28,29 . Latest research showed that the OAS1 could regulate the antitumour activity and toxicity of AZA and related drugs by OAS‐RNase L innate immune pathway 30 . APOBEC3H is a member of the apolipoprotein B mRNA‐editing enzyme catalytic polypeptide 3 families of proteins, and it induces somatic mutagenesis in cancer cells that drive tumour evolution and may manifest clinically as recurrence, metastasis and/or therapy resistance 31 .…”

Constitutive immune mechanisms: mediators of host defence and immune regulation

“…RNase L is a latent cytoplasmic exoribonuclease that is activated by 2′-5′ oligoadenylates produced by OASs 115 . Although OASs are highly interferon inducible, they are also expressed at a basal level and hence induce basal RNase L activity 116 . Importantly, this activity has been suggested to contribute to basal restriction of coronaviruses in myeloid cells, and hence to protect other cell types from infection 117 .…”

Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs

“…For example, OAS1 SNPs have also been implicated in altered cellular function leading to diseases including diabetes ( 37 ), multiple sclerosis ( 38 , 39 ), prostate cancers ( 40 ), and Sjögren's syndrome ( 41 , 42 ), as well as susceptibility to tuberculosis infection ( 43 ). OAS1 has also been recently implicated in cancer cell survival after treatment with DNA damaging agents ( 44 ) and in mediating the cytotoxicity of 5-azacytidine (AZA), a DNA methyltransferase inhibitor widely used in cancer treatment ( 45 ). Taken together, these studies suggest important roles for OAS1 in both innate immunity and other cellular processes that we have yet to fully elucidate.…”