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Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer

Oncogene volume 24, pages 4531–4539 (2005)Cite this article

Abstract

Histone deacetylase (HDAC) 6 is a subtype of the HDAC family; it deacetylates α-tubulin and increases cell motility. Here, we investigate the impact of an alteration of HDAC6 expression in estrogen receptor α (ER)-positive breast cancer MCF-7 cells, as we identified that HDAC6 is a novel estrogen-regulated gene. MCF-7 treated with estradiol showed increased expression of HDAC6 mRNA and protein and a four-fold increase in cell motility in a migration assay. Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells. In both cases, the cells changed in appearance from their original round shape to an axon-extended shape, like a neuronal cell. This HDAC6 accumulation caused the deacetylation of α-tubulin. Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of α-tubulin, leading to reduced cell motility. Tubacin, an inhibitory molecule that binds to the tubulin deacetylation domain of HDAC6, also prevented estradiol-stimulated cell migration. Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining. The prognostic analyses for these patients revealed no significant differences based on HDAC6 expression. However, subset analysis of ER-positive patients who received adjuvant treatment with TAM (n=67) showed a statistically significant difference in relapse-free survival and overall survival in favor of the HDAC6-positive group (P<0.02 and P<0.05, respectively). HDAC6 expression was an independent prognostic indicator by multivariate analysis (odds ratio=2.82, P=0.047). These results indicate the biological significance of HDAC6 regulation via estrogen signaling.

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Acknowledgements

We thank Drs Yoko Omoto and Mariko Muta for their help with our experiments. We are grateful to Drs Tso-Pang Yao and Yoshiharu Kawaguchi (Duke University) for their scientific suggestions for our work. This work was supported by the Sato Memorial Foundation for Cancer Research, the Sagawa Cancer Research Fund, and a grant from the Tokyo Metropolitan Government Bureau of Public Health.

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Authors and Affiliations

  1. Department of Clinical Trials and Research, Breast Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    Shigehira Saji, Masayo Kawakami, Makiko Hirose & Masakazu Toi

  2. Department of Molecular Medical Technology, Faculty of Medicine, Tohoku University, Sendai, Japan

    Shin-ichi Hayashi

  3. Division of Endocrinology, Saitama Cancer Center Research Institute, Saitama, Japan

    Nobuyuki Yoshida

  4. Department of Pathology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    Shin-ichiro Horiguchi & Nobuaki Funata

  5. Chemical Genetics Laboratory, RIKEN, Saitama, Japan

    Akihiro Itoh & Minoru Yoshida

  6. Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA

    Stuart L Schreiber

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  1. Shigehira Saji
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Correspondence to Shigehira Saji.

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Saji, S., Kawakami, M., Hayashi, Si. et al. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene 24, 4531–4539 (2005). https://doi.org/10.1038/sj.onc.1208646

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