Epigenetic Silencing of IRF7 and/or IRF5 in Lung Cancer Cells Leads to Increased Sensitivity to Oncolytic Viruses

Program in Molecular Biology and Genetics, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
PLoS ONE (Impact Factor: 3.23). 12/2011; 6(12):e28683. DOI: 10.1371/journal.pone.0028683
Source: PubMed


Defective IFN signaling results in loss of innate immunity and sensitizes cells to enhanced cytolytic killing after Vesticular Stomatitis Virus (VSV) infection. Examination of the innate immunity status of normal human bronchial epithelial cells Beas2B and 7 lung cancer cells revealed that the abrogation of IFN signaling in cancer cells is associated with greater sensitivity to VSV infection. The disruption of the IFN pathway in lung cancer cell lines and primary tumor tissues is caused by epigenetic silencing of critical interferon responsive transcription factors IRF7 and/or IRF5. Although 5-aza-2'-deoxycytidine treatment fails to reactivate IRF7 and IRF5 expression or protect cells from VSV infection, manipulating IFN signaling by altering IRF expression changes the viral susceptibility of these cells. Lung cancer cells can be partially protected from viral killing using IRF5+IRF7 overexpression, whereas IFN pathway disruption by transfection of siRNAs to IRF5+IRF7 increases cells' vulnerability to viral infection. Therefore, IRF5 and IRF7 are key transcription factors in IFN pathway that determine viral sensitivity of lung cancer cells; the epigenetically impaired IFN pathway in lung cancer tissues provides potential biomarkers for successful selective killing of cancer cells by oncolytic viral therapy.

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Available from: Michael A Tainsky
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    • "In many cancer cell types, specific genes associated with type I IFN signaling are transcriptionally downregulated or functionally inactive (Balachandran and Barber, 2004; Marozin et al., 2008, 2010; Moussavi et al., 2010; Zhang et al., 2010). Also, type I IFN mediated responses can be inhibited by MEK/ERK signaling, which is often upregulated in cancer cells (Noser et al., 2007), or by epigenetic silencing of IFN responsive transcription factors IRF7 or IRF5 (Li and Tainsky, 2011). Although all tested PDAC cell lines retain at least partially functional type I IFN signaling (Moerdyk-Schauwecker et al., 2013), it is likely that they have some dysregulation of this pathway, as type I IFN responses are generally anti-proliferative and pro-apoptotic (Stojdl et al., 2000; Vitale et al., 2007). "
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    ABSTRACT: Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retained their resistance to all tested VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "Indeed, genetic anolmalies of the interferon regulatory factors (IRFs), which belong to a family of transcription factors, have been identified in several carcinomas. Loss of expression of IRFs due to epigenetic modification of respective promoter regions have been observed with IRF5/7 in lung cancer (Li et al., 2011), IRF6 in cutaneous cancer (Botti et al., 2011) and IRF8 in multiple myeloma (Tshuikina et al., 2008), nasopharyngeal, esophageal (Lee et al., 2008) and colon cancers (McGough et al., 2008). Most of the IRFs share among themselves a highlyconserved N-terminal helix-turn-helix DNA-binding domain and a C-terminal protein binding domain called as IRF associated domain (IAD) (Ozato et al., 2007). "
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    ABSTRACT: Background: Interferon regulatory factor 6 (IRF6) is a transcription factor with distinct and conserved DNA and protein binding domains. Mutations within the protein binding domain have been significantly observed in subjects with orofacial cleft relative to healthy controls. In addition, recent studies have identified loss of expression of IRF6 due to promoter hypermethylation in cutaneous squamous cell carcinomas. Since mutational events occurring within the conserved domains are likely to affect the function of a protein, we investigated whether regions within the IRF6 gene that encodes for the conserved protein binding domain carried mutations in oral squamous cell carcinoma (OSCC). Materials and methods: Total chromosomal DNA extracted from 32 post surgical OSCC tissue samples were amplified using intronic primers flanking the exon 7 of IRF6 gene, which encodes for the major region of protein binding domain. The PCR amplicons from all the samples were subsequently resolved in a 1.2% agarose gel, purified and subjected to direct sequencing to screen for mutations. Results: Sequencing analysis resulted in the identification of a mutation within exon 7 of IRF6 that occurred in heterozygous condition in 9% (3/32) of OSCC samples. The wild type codon TTC at position 252 coding for phenylalanine was found to be mutated to TAC that coded for tyrosine (F252Y). Conclusions: The present study identified for the first time a novel mutation within the conserved protein binding domain of IRF6 gene in tissue samples of subjects with OSCC.
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    • "82. Liang, D., Y. Gao, X. Lin, et al. 2011. A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKepsilon. "
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    ABSTRACT: Abstract Effective immune responses require the coordinated activation and differentiation of several cell types, including T-cells, B-cells and myeloid cells. Abnormalities in the appropriate regulation of these processes underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Recent studies have revealed that, in addition to sequence-specific DNA-binding factors, the chromatin landscape of a cell can play a pivotal role in controlling these processes and in regulating the onset of autoimmunity. Interferon regulatory factors (IRFs) are emerging as critical regulators of the activation and differentiation of immune cells and deregulation in the expression and/or function of members of the IRF family has increasingly been linked to the pathogenesis of lupus. In this review, we will provide a brief overview of the role of different IRFs in immune responses and SLE development and discuss studies, which highlight the intricate relationship of this family of transcription factors with the epigenetic machinery.
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