title: Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-κB-dependent autophagy.
abstract: 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.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Shulak
authors.forename: Vladimir
authors.initials: V
authors.lastname: Beljanski
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiang
authors.forename: Sucharita M
authors.initials: SM
authors.lastname: Dutta
authors.forename: Julien
authors.initials: J
authors.lastname: Van Grevenynghe
authors.forename: S Mehdi
authors.initials: SM
authors.lastname: Belgnaoui
authors.forename: Thi Lien-Anh
authors.initials: TL
authors.lastname: Nguyên
authors.forename: Thomas
authors.initials: T
authors.lastname: Di Lenardo
authors.forename: O John
authors.initials: OJ
authors.lastname: Semmes
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects* / Q000235:genetics; D014779:Virus Replication; D000077337:Vorinostat
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D051996:Transcription Factor RelA; D000077337:Vorinostat