A screen for transcription factor targets of glycogen synthase kinase-3 highlights an inverse correlation of NFκB and androgen receptor signaling in prostate cancer
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1 Cell Biology and Stem Cells Unit, CIC bioGUNE, Spain
2 Department of Surgery and Cancer, Imperial College London, UK
3 Present address: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander 39011, Spain
Keywords: prostate cancer, glycogen synthase kinase-3, androgen receptor, NFκB transcription factor, Wnt signaling
Received: July 11, 2014 Accepted: August 02, 2014 Published: August 07, 2014
Abbreviations: GSK-3 (glycogen synthase kinase-3), AR (androgen receptor), GR (glucocorticoid receptor), CHIR (CHIR99021), BIO (BIO-Acetoxime), PS (PS1145), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), PCa (prostate cancer), DHT (dihydrotestosterone), TNF (tumor necrosis factor), and AP-2 (activating protein 2).
Expression of Glycogen Synthase Kinase-3 (GSK-3) is elevated in prostate cancer and its inhibition reduces prostate cancer cell proliferation, in part by reducing androgen receptor (AR) signaling. However, GSK-3 inhibition can also activate signals that promote cell proliferation and survival, which may preclude the use of GSK-3 inhibitors in the clinic. To identify such signals in prostate cancer, we screened for changes in transcription factor target DNA binding activity in GSK-3-silenced cells. Among the alterations was a reduction in AR DNA target binding, as predicted from previous studies, and an increase in NFκB DNA target binding. Consistent with the latter, gene silencing of GSK-3 or inhibition using the GSK-3 inhibitor CHIR99021 increased basal NFκB transcriptional activity. Activation of NFκB was accompanied by an increase in the level of the NFκB family member RelB. Conversely, silencing RelB reduced activation of NFκB by CHIR99021. Furthermore, the reduction of prostate cancer cell proliferation by CHIR99021 was potentiated by inhibition of NFκB signaling using the IKK inhibitor PS1145. Finally, stratification of human prostate tumor gene expression data for GSK3 revealed an inverse correlation between NFκB-dependent and androgen-dependent gene expression, consistent with the results from the transcription factor target DNA binding screen. In addition, there was a correlation between expression of androgen-repressed NFκB target genes and reduced survival of patients with metastatic prostate cancer. These findings highlight an association between GSK-3/AR and NFκB signaling and its potential clinical importance in metastatic prostate cancer.
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