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Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation

Oncogene volume 29, pages 5619–5629 (2010)Cite this article

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Abstract

Histone deacetylase inhibitors (HDACi) are potent anti-cancer agents for variety of cancer types. Suberoylanilide hydroxamic acid (SAHA) has been approved as a drug to treat cutaneous T cell lymphoma, and the combination of HDACi and other agents have been actively tested in many clinical trials. Adenovirus 5 early region 1A (E1A) has been shown to exhibit high tumor suppressor activity, and gene therapy using E1A has been tested in clinical trials. Here, we showed that proapoptotic activity of HDACi was robustly enhanced by E1A in multiple cancer cells, but not in normal cells. Moreover, we showed that combination of E1A gene therapy and SAHA showed high therapeutic efficacy with low toxicity in vivo ovarian and breast xenograft models. SAHA downregulated Bcl-XL and upregulated proapoptotic BH3-only protein Bim, whose expression was further enhanced by E1A in cancer cells. These alterations of Bcl-2 family proteins were critical for apoptosis induced by the combination in cancer cells. SAHA enhanced acetylation of histone H3 in Bim promoter region, while E1A upregulated Egr-1, which was directly involved in Bim transactivation. Together, our results provide not only a novel insight into the mechanisms underlying anti-tumor activity of E1A, but also a rationale for the combined HDACi and E1A gene therapy in future clinical trials.

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Acknowledgements

We thank Drs Jingwen Liu (Palo Alto Health Care System) and Thomas E Eling (National Institute of Health) for Egr-1 dominant negative expression plasmid and Egr-1 luciferase plasmid, respectively. We thank Dr Yongkun Wei for help in carrying out statistical analysis of xenograft experiments. We thank Drs Jennifer L. Hsu and Stephanie Miller for help in preparation of this paper. This work was supported by a SPORE Grant in ovarian cancer and breast cancer (P50 CA83639 and PO50 CA116199), the National Breast Cancer Foundation, MDACC China Medical University and Hospital Sister Institution Fund, Cancer Center Support Grant CA16672, DOH99-TD-C-111-005 Cancer Research Center of Excellence, Taiwan Department of Health, and the MARCUS Foundation. In memoriam, Mrs Serena Lin-Guo for her courageous fight against breast cancer.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Yamaguchi, C-T Chen, C-K Chou & M-C Hung

  2. Graduate School of Biomedical Sciences, University of Texas, Houston, TX, USA

    C-T Chen & M-C Hung

  3. Department of Experimental Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Pal

  4. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W Bornmann

  5. Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G N Hortobagyi

  6. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan

    M-C Hung

  7. Asia University, Taichung, Taiwan

    M-C Hung

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Correspondence to M-C Hung.

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The corresponding author, Dr Mien-Chie Hung, is an inventor on patents covering E1A as a therapeutic agent filed by the University of Texas MD Anderson Cancer. The remaining authors declare no conflict of interest.

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Yamaguchi, H., Chen, CT., Chou, CK. et al. Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation. Oncogene 29, 5619–5629 (2010). https://doi.org/10.1038/onc.2010.295

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