Combined genetic and epigenetic interferences with interferon signaling expose prostate cancer cells to viral infection

Abstract

Interferons (IFNs) induce anti-viral programs, regulate immune responses, and exert anti-proliferative effects. To escape anti-tumorigenic effects of IFNs, malignant cells attenuate JAK/STAT signaling and expression of IFN stimulated genes (ISGs). Such attenuation may enhance the susceptibility of tumor cells to oncolytic virotherapy. Here we studied genetic and epigenetic mechanisms of interference with JAK/STAT signaling and their contribution to susceptibility of prostate cancer cells to viral infection. Bioinformatics analysis of gene-expression in cohorts of prostate cancer patients revealed genetic and epigenetic interference with the IFN program. To correlate lack of IFN signaling and susceptibility to viral infection and oncolysis; we employed LNCaP prostate cancer cells as cellular model, and the human metapneumovirus and the epizootic hemorrhagic disease virus as infectious agents. In LNCaP cells, JAK1 is silenced by bi-allelic inactivating mutations and epigenetic silencing, which also silences ISGs. Chemical inhibition of epigenetic silencing partially restored IFN-sensitivity, induced low levels of expression of selected ISGs and attenuated, but failed to block, viral infection and oncolysis. Since viral infection was not blocked by epigenetic modifiers, and these compounds may independently-induce anti-tumor effects, we propose that epigenetic modifiers and virotherapy are compatible in treatment of prostate tumors defective in JAK1 expression and IFN signaling.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…The authors showed that treatment with both decitabine and trichostatin (TSA) restored JAK1 levels, which proved to be necessary for IFN cascade to occur. Danziger et al [147] further elaborated on this; they showed that the same epigenetic modifiers partially restored IFN signaling but, very relevantly, they also showed that this attenuated, but did not completely block viral infection in PCa cells. Given the known antitumor effect, the authors then conclude that these epigenetic drugs may be considered for combination with therapeutic viruses, since infection of cells is still possible.…”

“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in PCa is depicted in Table 3 [108,[141][142][143][144][145][146][147][148][149][150][151][152]. Some studies have focused on epigenetic regulation of response to IFN, where both methylation and acetylation can be involved, as demonstrated by Dunn and collaborators [141].…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…Importantly, this mechanism has been targeted in oncolytic virotherapy for cancer. Cancer cells that have low PKR expression are sensitive to oncolytic viruses [78][79][80] . Our study showed that ILF3 mediates the RNA editing-dependent regulation of PKR expression, suggesting that these two factors are intertwined in gene regulation.…”

Interleukin-6 and Interferon-α Signaling via JAK1–STAT Differentially Regulate Oncolytic versus Cytoprotective Antiviral States

“…In conjuncture with an inflammatory microenvironment, these molecular aberrations alter the activation state and function of a plethora of signal transduction pathways, including the JAK—signal transducer and signal transducer and activator of transcription (STAT) pathway ( 12 ). We and others have previously shown that a subset of PCa cells, and the LNCaP PCa cell line in particular, are defective in JAK1 expression ( 13 – 15 ). Notably, LNCaP cells express JAK2 and TYK2, but not JAK3, suggesting that multiple cytokine stimuli can be differently interpreted by these cells due to their expression pattern of JAK ( 16 ).…”

“…Notably, LNCaP cells express JAK2 and TYK2, but not JAK3, suggesting that multiple cytokine stimuli can be differently interpreted by these cells due to their expression pattern of JAK ( 16 ). Importantly, we have demonstrated that lack of JAK1 expression is associated with interferon-insensitivity and with hypersusceptibility of these cells to viral infections ( 15 ). In addition to interferon signaling, JAK1 mediates signaling by families of receptors that share the γc or gp130 subunits.…”