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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
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.
Insights
Inhibiting histone deacetylase 6 (HDAC6) in glioma cells enhances oncolytic herpes simplex virus type 1 (oHSV) replication. This finding offers a strategy to improve oncolytic viral (OV) therapy efficacy against brain tumors.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Oncolytic viral (OV) therapy utilizes engineered viruses to target and destroy cancer cells, stimulating an anti-tumor immune response.
- Tumor cells possess intrinsic defense mechanisms that can limit OV replication and spread.
- Histone deacetylase 6 (HDAC6) plays a role in cellular processes, including protein trafficking.
Purpose of the Study:
- To investigate the role of HDAC6 in glioma cell defense against oncolytic viral infection.
- To determine if inhibiting HDAC6 can enhance the replication of oncolytic viruses in glioma cells.
Main Methods:
- Utilized pharmacologic and genetic inhibition of HDAC6 in glioma cell lines and glioma-stem-like cells.
- Assessed replication of oncolytic herpes simplex virus type 1 (oHSV).
- Examined oHSV trafficking using electron microscopy and cellular localization studies.
Main Results:
- HDAC6 inhibition significantly increased oHSV replication in glioma cells.
- HDAC6 inhibition promoted the shuttling of post-entry oHSV to the nucleus.
- Glioma cells preferentially internalize oHSV via endocytosis rather than cell surface fusion.
Conclusions:
- HDAC6 acts as a cellular defense mechanism hindering oHSV nuclear entry and replication in glioma cells.
- Inhibiting HDAC6 represents a potential strategy to enhance oHSV therapy for brain tumors.
- Understanding OV-host cell interactions is crucial for optimizing oncolytic virotherapy outcomes.
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