Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-κB-dependent autophagy.
ISBN or ISSN
Journal of virology
Publication Date / Copyright Date
American Society For Microbiology
Vesicular stomatitis virus (VSV) is an oncolytic virus that induces cancer cell death through activation of the apoptotic pathway. Intrinsic resistance to oncolysis is found in some cell lines and many primary tumors as a consequence of residual innate immunity to VSV. In resistant-tumor models, VSV oncolytic potential can be reversibly stimulated by combination with epigenetic modulators, such as the histone deacetylase inhibitor vorinostat. Based on this reversible effect of vorinostat, we reasoned that critical host genes involved in oncolysis may likewise be reversibly regulated by vorinostat. A transcriptome analysis in prostate cancer PC3 cells identified a subset of NF-κB target genes reversibly regulated by vorinostat, as well as a group of interferon (IFN)-stimulated genes (ISGs). Consistent with the induction of NF-κB target genes, vorinostat-mediated enhancement of VSV oncolysis increased hyperacetylation of NF-κB RELA/p65. Additional bioinformatics analysis revealed that NF-κB signaling also increased the expression of several autophagy-related genes. Kinetically, autophagy preceded apoptosis, and apoptosis was observed only when cells were treated with both VSV and vorinostat. VSV replication and cell killing were suppressed when NF-κB signaling was inhibited using pharmacological or genetic approaches. Inhibition of autophagy by 3-methyladenine (3-MA) enhanced expression of ISGs, and either 3-MA treatment or genetic ablation of the autophagic marker Atg5 decreased VSV replication and oncolysis. Together, these data demonstrate that vorinostat stimulates NF-κB activity in a reversible manner via modulation of RELA/p65 signaling, leading to induction of autophagy, suppression of the IFN-mediated response, and subsequent enhancement of VSV replication and apoptosis.
Medical Specialties | Medicine and Health Sciences | Osteopathic Medicine and Osteopathy
Acetylation, Animals, Autophagy, Cell Line, Tumor, Chromatin, Cluster Analysis, Gene Knockdown Techniques, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Male, Mice, NF-kappa B, Oncolytic Virotherapy, Oncolytic Viruses, Prostatic Neoplasms, Protein Binding, Protein Transport, Transcription Factor RelA, Transcriptome, Vesicular stomatitis Indiana virus, Virus Replication
Shulak, Laura; Beljanski, Vladimir; Chiang, Cindy; Dutta, Sucharita M; Van Grevenynghe, Julien; Belgnaoui, S Mehdi; Nguyên, Thi Lien-Anh; Di Lenardo, Thomas; Semmes, O John; Lin, Rongtuan; and Hiscott, John, "Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-κB-dependent autophagy." (2014). Faculty Articles. 1568.