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p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y

Oncogene volume 22, pages 7762–7773 (2003)Cite this article

Abstract

Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.

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Acknowledgements

We thank Drs H Kojima, Y Yanase and AJ Fornace Jr for their generous gifts of materials. This work was supported by grants (H11-Seikatsu-018) for Research on Environmental Health from the Ministry of Health, Labour and Welfare of Japan; from the Smoking Research Foundation Grant for Biomedical Research; from the Grant-in-Aid for Scientific Research on Priority Areas (C) from The Ministry of Education, Culture, Sports, Science and Technology of Japan; and from the Grant-in-Aid for Encouragement of Young Scientists from the Japan Society for the Promotion of Science.

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  1. Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602-8566, Japan

    Tohru Hirose, Yoshihiro Sowa, Senye Takahashi, Shoichi Saito, Chikako Yasuda & Toshiyuki Sakai

  2. Molecular Medicine Laboratories, Institute for Drug Discovery Reseach, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

    Nobuaki Shindo & Kiyoshi Furuichi

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  1. Tohru Hirose
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Correspondence to Yoshihiro Sowa.

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Hirose, T., Sowa, Y., Takahashi, S. et al. p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene 22, 7762–7773 (2003). https://doi.org/10.1038/sj.onc.1207091

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