Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6

Angela Gibbs, Jacob Schwartzman, Vivianne Deng, Joshi Alumkal

    Research output: Contribution to journalArticle

    110 Citations (Scopus)

    Abstract

    High consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer in epidemiological studies. There is preliminary evidence that sulforaphane, derived from glucoraphanin found in a number of crucifers, may prevent and induce regression of prostate cancer and other malignancies in preclinical models, but the mechanisms that may explain these effects are not fully defined. Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90. AR is the central signaling pathway in prostate cancer, and its inhibition is used for both prevention and treatment of this disease. However, it is not known whether the effects of sulforaphane involve suppression of AR. We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes. Finally, sulforaphane inhibits HDAC6 deacetylase activity, and the effects of sulforaphane on AR protein are abrogated by overexpression of HDAC6 and mimicked by HDAC6 siRNA. The inactivation by sulforaphane of HDAC6-mediated HSP90 deacetylation and consequent attenuation of AR signaling represents a newly defined mechanism that may help explain this agent's effects in prostate cancer.

    Original languageEnglish (US)
    Pages (from-to)16663-16668
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume106
    Issue number39
    DOIs
    StatePublished - Sep 29 2009

    Fingerprint

    Histone Deacetylases
    Androgen Receptors
    Prostatic Neoplasms
    Acetylation
    sulforafan
    Proteasome Endopeptidase Complex
    Vegetables
    Small Interfering RNA
    Epidemiologic Studies
    Neoplasms

    Keywords

    • Acetylation
    • ERG
    • HSP90

    ASJC Scopus subject areas

    • General

    Cite this

    Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 6. / Gibbs, Angela; Schwartzman, Jacob; Deng, Vivianne; Alumkal, Joshi.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 39, 29.09.2009, p. 16663-16668.

    Research output: Contribution to journalArticle

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