Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma
Hiroshi Nakashima, … , Timothy P. Cripe, E. Antonio Chiocca
Hiroshi Nakashima, … , Timothy P. Cripe, E. Antonio Chiocca
Published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4269-4280. https://doi.org/10.1172/JCI80713.
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Research Article Oncology

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

Hiroshi Nakashima, Johanna K. Kaufmann, Pin-Yi Wang, Tran Nguyen, Maria-Carmela Speranza, Kazue Kasai, Kazuo Okemoto, Akihiro Otsuki, Ichiro Nakano, Soledad Fernandez, William F. Goins, Paola Grandi, Joseph C. Glorioso, Sean Lawler, Timothy P. Cripe, E. Antonio Chiocca

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Figure 5

Time-lapse imaging after infection of U251 glioma cells with a VP26-GFP–expressing HSV-1 in tubacin-treated and/or IFN-β–treated RFP-LAMP1–expressing U251 cells.

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Time-lapse imaging after infection of U251 glioma cells with a VP26-GFP–...
VP26-GFP–expressing HSV-1 (K26GFP) was added to RFP-LAMP1 stably expressing U251 cells after (C, D, G, and H) IFN-β pretreatment and/or (B, D, F, and H) tubacin treatment. GFP/RFP fluorescence signals were captured using time-lapse confocal microscopy. (A–D) The time at which each image was taken after infection is indicated on the top left and the bottom right. Scale bar: 20 μm. (E–H) Blue bars represent the percentages of intranuclear GFP puncta in total GFP-positive cells. Gray bars indicate that the presence of GFP-positive cells is 100%. Total counts of GFP-expressing cells and time (h.p.i.) after the infection are shown at bottom of bar plots. (See also Supplemental Figure 2.)