Carcinogenesis Advance Access originally published online on January 20, 2005
Carcinogenesis 2005 26(4):793-801; doi:10.1093/carcin/bgi021
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Carcinogenesis vol.26 no.4 © Oxford University Press 2005; all rights reserved.
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Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells
1 Departments of Urology and Biochemistry/Molecular Biology, Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA and 2 Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan 250012, P. R. China
* To whom correspondence should be addressed at: Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic/Foundation, Guggenheim Building 502, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 284 8336; Fax: +1 507 284 2384; Email: young.charles{at}mayo.edu
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.
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