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

Abstract

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 androgendependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is downregulated 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

Disease-proportional proteasomal degradation of missense dystrophins

“…The heat shock activator gedunin had a similar effect on ubiquitination in the cell, emphasizing the close connection between the heat shock and the ubiquitin-proteasome pathways. These data also corroborate previous studies that have found Hsp90 inhibition increases ubiquitination (42). The heat shock system was confirmed to be up-regulated upon treatment with each of the small-molecule compounds (Fig.…”

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

“…Besides known natural and synthetic agents, a number of different bioactive food components, such as quercitin (Aalinkeel et al 2008), genistein (Basak et al 2008), and epigallocatechin-3-gallate (Tran et al 2010), were also identified as potent HSP90 inhibitors. Modulation of post-translational mechanisms is an important approach to interfere with the regulation of HSP90.…”

“…Classical inhibitors like geldanamycin and its derivates as well as synthetic molecules block the ATPase-coupled chaperone cycle and consign bound client proteins for ubiquitination and proteosomal degradation (Pearl et al 2008). Targeting molecules that are involved in the regulation of HSP90, as for example histone deacetylase (HDAC) 6, is an alternative approach to inhibit chaperone activity (Pearl et al 2008) and was, inter alia, demonstrated for genistein (Basak et al 2008). Quercitin (Aalinkeel et al 2008) and epigallocatechin-3-gallate (Yin et al 2009) are further nutrition-related compounds with HSP90-inhibiting potential.…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…50 Genistein, an isoflavone, inhibits EGFR tyrosine kinase, 51 and also inhibits the Hsp90 deacetylase (HDAC6)-Hsp90 co-chaperone function, which downregulates the expression of androgen receptor in androgen-dependent prostate cancer cell lines. 52 Quercetin, a flavonoid, inhibits cancer cells that over-express ErbB2 (Her-2/neu) trans-membrane tyrosine kinase and downregulates the downstream PI3K-Akt signaling pathway. 53 Novobiocin binds to the C-terminal domain of Hsp90 and disrupts the Bcr-Abl/Hsp90 complex.…”