Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function.

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Research Abstract Details 

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Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Abstract Text:

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90. [Mol Cancer Ther 2008;7(10):3195-202].

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Publishing Authors By Initials

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Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Molecular cancer therapeutics

VOLUME: 7

Page Numbers: 3195-202

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ISSN: 1535-7163

DAY: 14

MONTH: Oct

YEAR: 2008

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Information

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LANGUAGE: eng

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AFFILIATION: Urology Research Center (112F), San Francisco Veterans Affairs Medical Center and University of California, San Francisco, 4150 Clement Street, San Francisco, CA 94121. Rdahiya@urology.ucsf.edu.

Country: United States

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MEDLINETA: Mol Cancer Ther

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