Androgen Receptor Overexpression in Prostate Cancer Linked to Purα Loss from a Novel Repressor Complex

Abstract

Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5 ¶-untranslated region contains PurA and hnRNP-K. PurA expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AILNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored PurA expression reduced AR at the transcription and protein levels. PurA knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored PurA protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. PurA is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring PurA and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC. [Cancer Res 2008;68(8):2678-88]

Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (Review)

“…Significantly, it has been found that this suppressor protein(s) could be induced to re-express in AI cells through histone deacetylase inhibitors, such as trichostatin A, sodium butyrate or suberoylanilide hydroxamic acid (SAHA). Consequently, a normal AR function was restored as indicated by regaining an androgen-dependent phenotype and apoptotic sensitivity to chemotherapeutic agents (24)(25)(26)(27). Consistent with these findings, histone deacetylase inhibitors LAQ824 and SAHA have also been reported to repress AR at both the transcriptional and posttranslational levels (28,29).…”

Heterogeneous nuclear ribonucleoprotein K: altered pattern of expression associated with diagnosis and prognosis of prostate cancer

“…Whatever the mechanism involved, hnRNP K might play a role in the regulation of AR gene. Wang et al (2008) showed that in LNCaP cells 5 0 -untranslated region of the AR promoter harbours a suppressor element, which is directly bound hnRNP and Pura, but only the regulation of this latter is crucial for the repression of AR levels. Vice versa Shi et al (2008) have reported that transcriptional downregulation of AR in the aging rat liver and in oxidatively stressed hepatoma cells involve hnRNP K through the interactions with PARP-1 and the first may serve as a stabilising docking platform for the activating complex that governs AR stimulation; in this model, silencing of hnRNP K decreased AR expression.…”

“…Until now, very little is known about the behaviour of hnRNP K in PCa; Nagano et al (2004) demonstrated that the hnRNP K was strongly overexpressed in PCa with respect to normal cell lines derived from the same patient and that the protein was differentially modulated in two cell lines by INF. More recently, Wang et al (2008) have shown that a novel transcriptional repressor complex containing Pura and hnRNP K binds the androgen receptor (AR) gene both in cell lines and in human prostate tissues. These results prompted us to better characterise the role of this protein in PCa.…”

Tissue control of androgen action: The ups and downs of androgen receptor expression

“…This suppression of the pur-α gene leads to attenuated pur-α downregulation of the hAR gene and contributes to increased AR expression (Wang et al 2008).…”