Journal Article

Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells

Huiqing Yuan, Aiyu Gong and Charles Y.F. Young

in Carcinogenesis

Volume 26, issue 4, pages 793-801
Published in print April 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi021
Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells

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The transactivation function of the human androgen receptor (AR) can be regulated by several coregulators that may be either positive or negative. Ubiquitous transcription factor Sp1 not only regulates the basal expression of the AR but also acts as its coregulator. Our previous study has shown that quercetin, one of the main polyphenols, can effectively inhibit the expression and function of the AR. The present study is to address if quercetin may affect Sp1's action on AR transactivation activity in human prostate adenocarcinoma cell lines, LNCaP and PC-3. First, we showed that indeed in transient transfections Sp1 could enhance transcriptional activity of the AR promoter and of androgen upregulated gene promoters, i.e. the prostate-specific antigen and the hK2 genes. Interestingly, the enhancing activity of Sp1 could be repressed by quercetin. The gel shift and western blot analyses indicated that the specific DNA motif binding activity of Sp1 and its protein levels were not altered by quercetin. However, the state of interaction of Sp1 with the AR treated by quercetin plus androgen was different from that by androgen treatment or none as demonstrated by coimmunoprecipitation experiments and glutathione S-transferase (GST) pull-down assays. Moreover, we showed that quercetin caused changes in post-translational modification of AR protein. The above findings strongly suggest that changes induced by quercetin in post-translational modification of the AR and in states of physical interaction of Sp1 with the AR may be critical for the attenuation of AR's function.

Keywords: AR, androgen receptor; AP-1, activator protein-1; ARE, androgen responsive element; β-gal, β-galactosidase; DTT, dithiothreitol; GST, glutathione S-transferase; hK2, human glandular kallikrein; Mib, mibolerone; PBS, phosphate buffered saline; PMSF, phenylmethanesulfonyl fluoride; PSA, prostate-specific antigen; Sp1, promoter specificity protein 1; CREB, cAMP response element binding protein; CBP, CREB-binding protein

Journal Article.  6908 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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