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An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA

Cancer Gene Therapy volume 20, pages 351–357 (2013)Cite this article

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Abstract

Histone deacetylase (HDAC) inhibitors are used in treating certain human malignancies. Our laboratories demonstrated their capability in enhancing antitumor effect of DNA vaccine driven by an RNA polymerase II (RNA pol II) promoter. However, it is unknown whether HDAC inhibitors enhance the therapeutic short hairpin RNA (shRNA) expressed by an RNA polymerase III (RNA pol III) promoter. We investigated whether HDAC inhibitors augmented antitumor effect of indoleamine 2,3 dioxygenase (IDO) shRNA. HDAC inhibitor OSU-HDAC42 and suberoylanilide hydroxamic acid enhanced RNA pol III-driven U6 and H1 promoter activity in three different cell types in vitro: 293, NIH3T3 and dendritic cell line DC2.4. Subcutaneous injection of OSU-HDAC42 enhanced U6 and H1 promoter activity on abdominal skin of mice in vivo. Combination of IDO shRNA and OSU-HDAC42 increased antitumor effect of IDO shRNA in MBT-2 murine bladder tumor model. IDO shRNA induced tumor-infiltrating CD8+ and CD4+ T cells, whereas OSU-HDAC42 treatment induced tumor-infiltrating CD4+ T cells. Combination of OSU-HDAC42 and IDO shRNA further induced tumor-infiltrating natural killer cells and enhanced interferon-γ in lymphocytes, but suppressed interleukin (IL)-4 expression of lymphocytes. In addition, OSU-HDAC42 treatment did not alter mRNA expression of IL-12 and tumor necrosis factor-α. In conclusion, HDAC inhibitor OSU-HDAC42 may serve as adjuvant of the therapeutic shRNA expressed by an RNA pol III promoter.

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Acknowledgements

This study is supported by the grant to MD Lai, NSC-100-2325-B-006-008, 101-2325-B-006-007 and 101-2320-B-006-028-MY3 from the National Science Council, Taiwan

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    M-C Yen, T-Y Weng, C-Y Chen, C-Y Wang & M-D Lai

  2. Infectious diseases and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan

    M-C Yen & M-D Lai

  3. Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    T-Y Weng, C-Y Wang & M-D Lai

  4. Department of Senior Citizen Service Management, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan

    Y-L Chen

  5. Institute of Medical Technology, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan

    C-C Lin

  6. Department of Medical Education and Research, Taichung-Veterans General Hospital, Taichung, Taiwan

    C-C Lin

  7. Department of Medical Laboratory Science and BioTechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    H-L Chao

  8. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    C-S Chen

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Correspondence to M-D Lai.

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Dr Chen conducts a clinical trial on OSU-HDAC42 currently. The remaining authors declare no conflict of interest.

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Yen, MC., Weng, TY., Chen, YL. et al. An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA. Cancer Gene Ther 20, 351–357 (2013). https://doi.org/10.1038/cgt.2013.27

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