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

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Interferons (IFNs) are crucial for antiviral defense and immune regulation, but cancer cells often evade their anti-tumor effects by disrupting JAK/STAT signaling.
• Impaired IFN signaling and reduced expression of IFN-stimulated genes (ISGs) can make tumors more vulnerable to oncolytic virotherapy.

Purpose of the Study:

• To investigate the genetic and epigenetic mechanisms underlying JAK/STAT pathway interference in prostate cancer.
• To determine how these mechanisms affect prostate cancer cell susceptibility to viral infection and oncolysis.

Main Methods:

• Bioinformatics analysis of prostate cancer gene expression data to identify IFN pathway alterations.
• Utilizing LNCaP prostate cancer cells and human metapneumovirus/epizootic hemorrhagic disease virus for in vitro studies.
• Employing chemical inhibitors of epigenetic silencing to assess restoration of IFN sensitivity.

Main Results:

• Prostate cancer cells (LNCaP) exhibit JAK1 silencing via mutations and epigenetic mechanisms, leading to suppressed ISGs.
• Epigenetic silencing inhibition partially restored IFN sensitivity and ISG expression but did not fully block viral infection or oncolysis.
• Viral infection and oncolysis were not completely inhibited by epigenetic modifiers.

Conclusions:

• Prostate cancer cells with impaired JAK1/IFN signaling are susceptible to oncolytic viruses.
• Epigenetic modifiers and oncolytic virotherapy show compatibility for treating prostate tumors with defective JAK1 expression and IFN signaling.
• Combined epigenetic therapy and virotherapy may offer a novel treatment strategy for specific prostate cancer subtypes.