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Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90

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Abstract

Histone deacetylase 6 (HDAC6) inhibition, recently, has been shown to promote the acetylation of heat-shock protein 90 (Hsp90) and disrupt its chaperone function. Her-2 oncoprotein is identified as a client protein of Hsp90. Therefore, in this study we examined the effect of carbamazepine, which could inhibit HDAC on Hsp90 acetylation and Her-2 stability. The results of this study demonstrate that while carbamazepine had no effect on the Her-2 mRNA level, it induced Her-2 protein degradation via the proteasome pathway by disrupting the chaperone function of Hsp90 in SK-BR-3 cells. Mechanistically, carbamazepine could enhance the acetylation of α-tubulin, indicating its inhibitory effect on HDAC6. Functionally, carbamazepine could synergize with trastuzumab or geldanamycin to promote Her-2 degradation and inhibit breast cancer cell proliferation. Thus, this study has potential clinical implications by providing a promising strategy to overcome the development of resistance against trastuzumab therapy for breast cancer.

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Acknowledgment

This study was supported by grants from Heilongjiang Provincial Bureau of Health (2009015) and from the Tumor Hospital of Harbin Medical University (JJ2007-02).

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Authors and Affiliations

  1. The Breast Department of the Third Affiliated Hospital of Harbin Medical University, 150040, Harbin, People’s Republic of China

    Qingwei Meng, Xuesong Chen, Lichun Sun, Changhong Zhao, Guangjie Sui & Li Cai

Authors
  1. Qingwei Meng
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  2. Xuesong Chen
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  3. Lichun Sun
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  4. Changhong Zhao
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  5. Guangjie Sui
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  6. Li Cai
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Corresponding author

Correspondence to Li Cai.

Additional information

Qingwei Meng, Xuesong Chen, and Lichun Sun have contributed equally to this study.

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Meng, Q., Chen, X., Sun, L. et al. Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90. Mol Cell Biochem 348, 165–171 (2011). https://doi.org/10.1007/s11010-010-0651-y

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  • DOI: https://doi.org/10.1007/s11010-010-0651-y

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