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

M. C. Yen, T. Y. Weng, Y. L. Chen, C. C. Lin, C. Y. Chen, C. Y. Wang, H. L. Chao, C. S. Chen, M. D. Lai

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)351-357
Number of pages7
JournalCancer Gene Therapy
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 1 2013
Externally publishedYes

Keywords

  • H1 promoter
  • IDO shRNA
  • indoleamine 2,3-dioxygenase
  • OSU-HDAC42
  • RNA polymerase I.I.I.
  • U6 promoter

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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  • Cite this

    Yen, M. C., Weng, T. Y., Chen, Y. L., Lin, C. C., Chen, C. Y., Wang, C. Y., Chao, H. L., Chen, C. S., & Lai, M. D. (2013). An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA. Cancer Gene Therapy, 20(6), 351-357. https://doi.org/10.1038/cgt.2013.27