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Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells

Oncogene volume 23, pages 6261–6271 (2004)Cite this article

Abstract

Death receptor 5 (DR5) is a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. Here, we report that histone deacetylase inhibitors (HDACIs) such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA) upregulated DR5 expression in various human malignant tumor cells. An RNase protection assay demonstrated that HDACIs induced DR5 mRNA markedly but not that of other death receptor family members in Jurkat cells. HDACIs increased DR5 mRNA and protein in a dose- and time-dependent manner. We also show TSA increased DR5 promoter activity using a luciferase promoter assay. Furthermore, we demonstrated that HDACIs strongly sensitized exogenous soluble recombinant human TRAIL-induced apoptosis synergistically in Jurkat and HL-60 cells that were tolerant to TRAIL alone. The combined use of HDACIs and TRAIL in suboptimal concentrations induced Bid cleavage and activation of caspase-8, -10, -3, and -9. Human recombinant DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 and -10 inhibitors efficiently reduced apoptosis induced by cotreatment with HDACIs and TRAIL. Furthermore, TSA did not significantly induce DR5 protein and HDACIs did not enhance TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. These results suggest that this combined treatment with HDACIs and TRAIL is a promising strategy for new cancer therapeutics.

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Abbreviations

DR5:

death receptor 5

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

TNF:

tumor necrosis factor

HDACIs:

histone deacetylase inhibitors

TSA:

trichostatin A

SAHA:

suberoylanilide hydroxamic acid

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

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Acknowledgements

We thank Dr Takafumi Kimura (Department of Hygiene, Kyoto Prefectural University of Medicine) for very helpful experimental advice. This work was supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology, a grant (H11-Seikatsu-018) for Research on Environmental Health from the Ministry of Health, Labor, and Welfare of Japan, and the SRF Grant for Biomedical Research.

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Authors and Affiliations

  1. Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramcahi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Susumu Nakata, Tatsushi Yoshida, Mano Horinaka, Takumi Shiraishi, Miki Wakada & Toshiyuki Sakai

  2. Department of Applied Biochemistry, Kyoto Prefectural University, Kyoto, 606-8522, Japan

    Mano Horinaka

  3. Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

    Takumi Shiraishi

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Correspondence to Toshiyuki Sakai.

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Nakata, S., Yoshida, T., Horinaka, M. et al. Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 23, 6261–6271 (2004). https://doi.org/10.1038/sj.onc.1207830

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