2. Academic Validation
  3. Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

  • Sci Rep. 2018 Aug 1;8(1):11554. doi: 10.1038/s41598-018-28421-x.
Baojie Lv 1 2 3,  Jingjing Li 1 3,  Meng Li 3,  Yujie Zhuo 2,  Ke Ren 4,  Erguang Li 5 6,  Guang Yang 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
  • 2 Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China.
  • 3 Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
  • 4 School of Laboratory Medicine, Chengdu Medical College, Chengdu, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China. erguang@nju.edu.cn.
  • 6 Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. erguang@nju.edu.cn.
  • 7 Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China. gyangnj@qq.com.
  • 8 Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China. gyangnj@qq.com.
PMID: 30068949 DOI: 10.1038/s41598-018-28421-x
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.

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