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Histone deacetylase inhibitor FK228 suppresses the Ras–MAP kinase signaling pathway by upregulating Rap1 and induces apoptosis in malignant melanoma

Oncogene volume 25, pages 512–524 (2006)Cite this article

Abstract

Histone deacetylase (HDAC) inhibitors are expected to be effective for refractory cancer because their mechanism of action differs from that of conventional antineoplastic agents. In this study, we examined the effect of the HDAC inhibitor FK228 on malignant melanoma, as well as its molecular mechanisms. FK228 was highly effective against melanoma compared with other commonly used drugs. By comparing the gene expression profiles of melanoma cells and normal melanocytes, we defined a subset of genes specifically upregulated in melanoma cells by FK228, which included Rap1, a small GTP-binding protein of the Ras family. The expression of Rap1 mRNA and protein increased in FK228-treated melanoma cells in both a dose- and a time-dependent manner. A decrease in the phosphorylation of c-Raf, MEK1/2, and ERK1/2 was accompanied by an increase in Rap1 expression in both FK228-treated and Rap1-overexpressing cells. Inhibition of Rap1 upregulation by small interfering RNA (siRNA) abrogated the induction of apoptosis and suppression of ERK1/2 phosphorylation in FK228-treated melanoma cells. These results indicate that the cytotoxic effects of FK228 are mediated via the upregulation of Rap1. Furthermore, we found that Rap1 was overexpressed and formed a complex with B-Raf in melanoma cell lines with a V599E mutation of B-Raf. The siRNA-mediated abrogation of Rap1 overexpression increased the viability of these cells, suggesting that Rap1 is also an endogenous regulator of Ras–MAP kinase signaling in melanomas.

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Acknowledgements

We are grateful to Ms Noriko Hayashi and Ms Izumi Nozawa for their excellent technical assistance. We thank Drs Hideshi Ishii, Kazuhiro Ishikawa, Ken Futaki, and Taeko Wada (Jichi Medical School) for helpful discussions. This work was supported by High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT 2002–2006, and by a grant from the Japan Medical Association (to YF).

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Authors and Affiliations

  1. Division of Stem Cell Regulation, Jichi Medical School, Yakushiji, Minamikawachi-machi, Tochigi, Japan

    Y Kobayashi, T Kobayashi, K Sutheesophon & Y Furukawa

  2. Department of Dermatology, Jichi Medical School, Yakushiji, Minamikawachi-machi, Tochigi, Japan

    Y Kobayashi, M Ohtsuki & T Murakami

  3. Divison of Organ Transplantation, Jichi Medical School, Yakushiji, Minamikawachi-machi, Tochigi, Japan

    T Murakami

  4. Department of Nephrology, Jichi Medical School, Yakushiji, Minamikawachi-machi, Tochigi, Japan

    T Kobayashi & E Kusano

  5. Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

    H Kitayama

  6. Division of Medical Oncology, Tochigi Cancer Center, Yonan, Utsunomiya, Tochigi, Japan

    Y Kano

  7. Department of Dermatology, Jikei University School of Medicine, Nishi-Shinbashi, Minato-ku, Tokyo, Japan

    H Nakagawa

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  1. Y Kobayashi
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Correspondence to Y Furukawa.

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Kobayashi, Y., Ohtsuki, M., Murakami, T. et al. Histone deacetylase inhibitor FK228 suppresses the Ras–MAP kinase signaling pathway by upregulating Rap1 and induces apoptosis in malignant melanoma. Oncogene 25, 512–524 (2006). https://doi.org/10.1038/sj.onc.1209072

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