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

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.

Effects of indoleamine 2, 3‐dioxygenase (IDO) silencing on immunomodulatory function and cancer‐promoting characteristic of adipose‐derived mesenchymal stem cells (ASCs)

“…IDO1 gene silencing in ASCs was associated with elevated expression of IFN‐γ in PBLs in comparison to control groups, whereas Th2 cells slightly reduced in PBLs cocultured with IDO1‐silenced ASCs relative to scramble group. In correlation with our results, Yen et al (2013) indicated that IL‐4 was suppressed while IFN‐γ expression was significantly elevated in murine model with bladder tumor after vaccination with IDO shRNA. Also, the analysis of immune responses in lymph nodes of metastatic melanoma patients who were vaccinated by IDO1 siRNA‐transfected DCs indicated significantly elevated level of IFN‐γ (Sioud et al, 2016).…”

Neutrophils are Essential in Short Hairpin RNA of Indoleamine 2,3- Dioxygenase Mediated-antitumor Efficiency

“…11 Because low pressure gene gun efficiently deliver plasmid into skin dendritic which migrate to inguinal lymph nodes or spleen, 32 skin delivery of IDO shRNA suppresses expression in CD11C + dendritic cells in tumor draining lymph nodes and plasmatocytoid dendritic cells in spleen but did not affect IDO expression in total cells of lymph node, spleen, and tumor. 10,11,25 Thus, we suppose that the levels of tryptophan metabolites are not changed in spleen and acyl hydrogen receptor pathway might not involve in IDO shRNA-mediated immune responses. In this study, IDO shRNA was delivered by intramuscular injection.…”

“…11,25 After gene gun delivery of IDO shRNA, IDO expression in dendritic cells was suppressed. However, The IDO expression of total splenocytes was not altered.…”

Chidamide, a histone deacetylase inhibitor, functions as a tumor inhibitor by modulating the ratio of Bax/Bcl-2 and P21 in pancreatic cancer

“…Chidamide functions as a HDAC inhibitor which is newly designed and synthesized in China (8) and may specifically suppress the level of type I HDACs. Increasing findings, from in vitro studies of tumor cell lines to in vitro studies of animal tumor models, support that Chidamide is a potential therapeutic drug in the treatment of a variety of cancers such as hepatocellular carcinoma, lymphoma cancer and bladder tumor (12,18,19). Despite substantial progress in understanding the effect of Chidamide on cancer, the underlying molecular mechanism remains to be determined.…”