title: Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma.
abstract: Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Kaufmann
authors.forename: Pin-Yi
authors.initials: PY
authors.lastname: Wang
authors.forename: Tran
authors.initials: T
authors.lastname: Nguyen
authors.forename: Maria-Carmela
authors.initials: MC
authors.lastname: Speranza
authors.forename: Kazue
authors.initials: K
authors.lastname: Kasai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okemoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Otsuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
authors.forename: Sean
authors.initials: S
authors.lastname: Lawler
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics; D000813:Anilides / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D002213:Capsid / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000821:virology; D004705:Endocytosis / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008247:Lysosomes / Q000821:virology; D008868:Microtubule Proteins; D008870:Microtubules / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D018874:Spheroids, Cellular; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008868:Microtubule Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D012367:RNA, Viral; D014404:Tubulin; C474316:tubacin; D014635:Valproic Acid; D016899:Interferon-beta; D000123:Acetyltransferases; C000627069:ATAT1 protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases