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Regulation of ERα Signaling Pathway in Neuronal HN10 Cells: Role of Protein Acetylation and Hsp90

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Abstract

Estrogen has a variety of neuroprotective effects but the molecular basis of its function is still mainly unclear. Estrogen receptor (ER) signaling is highly dependent on posttranslational modifications and the assembly of coactivator and corepressor complexes. Several proteins involved in ERα signaling have recently been found to be acetylated, including ERα itself and Hsp90, a key chaperone in the functional regulation of ERα. ERα complexes also contain histone deacetylases (HDAC) which repress transactivation. Our purpose was to clarify the role of protein acetylation and Hsp90 function in the ERE-mediated ERα signaling in neuronal HN10 cells. We observed that increasing protein/histone acetylation status with trichostatin A, a potent HDAC inhibitor, increased the 17β-estradiol (E2)-induced transactivation of ERE-driven luciferase in non-transfected cells, and even more extensively in pERα-transfected cells. E2-induced ERE-driven transactivation was blocked by ICI 182.780. Several ER antagonists, such as raloxifene and tamoxifen, were unresponsive. Valproate, an antiepileptic drug which is recently characterized as a HDAC inhibitor, was also able to potentiate the E2-induced ERE-transactivation. Inhibition of the function of Hsp90 chaperone with geldanamycin strongly inhibited the E2-induced ERE-transactivation. Overexpression of SIRT2 protein deacetylase did not inhibit the acetylation-potentiated ERE-driven transactivation indicating that SIRT2 deacetylase is not involved in ERα signaling. Our results reveal that ERα signaling is dependent on protein acetylation and epigenetic regulation.

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Acknowledgments

This study was supported by grants from the Academy of Finland (J.O., A.S.), University Hospital of Kuopio (EVO 5510) and the University of Kuopio (T.S., K.K. and A.S.), Finland. The authors thank Prof. Pirkko Härkönen for kindly providing plasmids and Dr. Ewen MacDonald for checking the language of the manuscript.

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Authors and Affiliations

  1. Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Tiina Suuronen, Johanna Ojala & Antero Salminen

  2. Department of Ophthalmology, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Juha M. T. Hyttinen & Kai Kaarniranta

  3. Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden

    Anders Thornell

  4. Department of Biosciences, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Sergiy Kyrylenko

  5. Institute of Molecular Biology and Genetics NASU, 03143, Kyiv, Ukraine

    Sergiy Kyrylenko

  6. Department of Neurology, University Hospital of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland

    Antero Salminen

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  1. Tiina Suuronen
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  2. Johanna Ojala
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  3. Juha M. T. Hyttinen
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  7. Antero Salminen
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Correspondence to Antero Salminen.

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Suuronen, T., Ojala, J., Hyttinen, J.M.T. et al. Regulation of ERα Signaling Pathway in Neuronal HN10 Cells: Role of Protein Acetylation and Hsp90. Neurochem Res 33, 1768–1775 (2008). https://doi.org/10.1007/s11064-008-9622-z

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  • DOI: https://doi.org/10.1007/s11064-008-9622-z

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