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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

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Hydrogen sulfide represses androgen receptor transactivation by targeting at the second zinc finger module

Kexin Zhao, Shuangshuang Li, Lingyun Wu

    The Journal of Biological Chemistry
    |June 20, 2014
    PubMed

    Insights

    Hydrogen sulfide (H2S) inhibits prostate cancer cell growth, particularly in antiandrogen-resistant cells. Reduced H2S production is linked to resistance, suggesting H2S as a potential therapy for castration-resistant prostate cancer.

    Area of Science:

    • Oncology
    • Biochemistry
    • Molecular Biology

    Background:

    • Androgen receptor (AR) signaling drives prostate cancer progression.
    • Therapeutic resistance, particularly antiandrogen resistance, remains a major clinical challenge.
    • Hydrogen sulfide (H2S), a gasotransmitter, has emerging roles in cellular regulation.

    Purpose of the Study:

    • To investigate the role of H2S in regulating AR signaling.
    • To determine H2S's effect on androgen-independent prostate cancer cell growth.
    • To explore H2S as a potential therapeutic agent for castration-resistant prostate cancer.

    Main Methods:

    • Cell proliferation assays in androgen-dependent and resistant prostate cancer cell lines.
    • Analysis of cystathionine γ-lyase (CSE) expression in prostate cancer tissues and cells.
    • Gene expression analysis of AR-targeted genes (PSA, TMPRSS2).
    • Assays for AR binding to PSA promoter and androgen-responsive element (ARE) luciferase activity.
    • Investigation of AR post-translational modification (S-sulfhydration) and its impact on AR dimerization.

    Main Results:

    • H2S inhibited proliferation in both androgen-dependent and antiandrogen-resistant prostate cancer cells.
    • Reduced CSE expression, a key H2S-producing enzyme, was observed in resistant cells and human prostate cancer tissues.
    • Overexpression of CSE restored sensitivity to antiandrogen treatment in resistant cells.
    • H2S repressed AR-targeted gene expression (PSA, TMPRSS2) and inhibited AR binding to the PSA promoter.
    • AR was found to be S-sulfhydrated by H2S, affecting AR dimerization and DNA binding.

    Conclusions:

    • Reduced CSE/H2S signaling contributes to the development of antiandrogen resistance in prostate cancer.
    • Sufficient H2S levels can inhibit AR transactivation and AR signaling.
    • H2S holds therapeutic potential for treating castration-resistant prostate cancer.

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