Abstract
Adenovirus-based vectors are among the most commonly used platforms for gene delivery and gene therapy studies. One of the obstacles for potential application is dose-related toxicity. We show here that adenovirus infection and Ad-mediated gene delivery can be enhanced by inhibitors of bromodomain and extra-terminal (BET) family proteins. We showed that JQ1, but not its inactive enantiomer (−)-JQ1, dose-dependently promoted Ad infection and Ad-mediated gene delivery in both epithelial and lymphocyte cells. Given orally, JQ1 also enhanced transgene expression in a murine tumor model. Inhibitors of histone deacetylases (HDACi) are among the commonly reported small molecule compounds which enhance Ad-mediated gene delivery. We found that JQ1 treatment did not cause histone acetylation nor expression of Ad attachment receptor CAR. Instead, JQ1 treatment induced an increase in BRD4 association with CDK9, a subunit of P-TEFb of transcription elongation. Concurrently, we showed that CDK9 inhibition blocked Ad infection and JQ1 enhancement on the infection. The study exemplifies the potentials of BET inhibitors like JQ1 in oncolytic virotherapy.
Highlights
Adenovirus-based vectors are among the most commonly utilized platforms for gene delivery in cell biology studies and in gene therapy applications
To investigate whether bromodomain and extra-terminal (BET) bromodomain inhibition plays a role in Ad infection, A549 cells were treated with well-characterized BRD4 inhibitors 1 h prior to Ad2 infection
We found that BRD4 inhibitors like JQ1 promoted Ad infection and Ad-mediated gene delivery
Summary
Adenovirus-based vectors are among the most commonly utilized platforms for gene delivery in cell biology studies and in gene therapy applications. It is known that viruses utilize host cell translation machinery for protein synthesis, which can be a potential target for enhanced Ad-mediated gene delivery. It is known that the adenoviral E1A protein causes significant reduction in cellular levels of lysine acetylation of histone H321,22 and can disturb the normal cellular interaction between p300/CBP and its associated histone acetylase[23,24]. It is not clear how epigenetic factors may affect adenovirus replication or infection, limited evidence suggests that histone modification is involved in the regulation of adenovirus gene expression[17,25]. Inhibitors of histone deacetylase (HDACi) have been demonstrated to promote both wild type Ad infection and gene delivery efficiency by replicative defective Ad viruses[19,26,27,28]
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