Abstract
Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to AR-reactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c-Myc. The functional cross-talk between c-Myc and FKBP52 was established using c-Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non-canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52.
Highlights
Androgens are known to be major stimulators of prostate tumor proliferation, as evident from initial arrest of metastatic growth by androgen ablation[1]
The present study investigated differential expression of genes pertaining to the androgen receptor (AR) signaling pathway between Benign prostatic hyperplasia (BPH) and prostate cancer patient samples, in anticipation that detection of specific genes and their associated components may provide the molecular cues underlying the mechanism of neoplastic development of the prostate gland and hold promises to eventually identify specific markers that demarcate disease states and progression
In order to verify the authenticity of the prostate cancer and BPH tissues before the samples were subjected to microarray analyses, expression of several genes known to be functionally associated with androgen responsive pathway was examined using semi-quantitative and quantitative RT-PCR, western blot hybridization and immunohistochemistry
Summary
Androgens are known to be major stimulators of prostate tumor proliferation, as evident from initial arrest of metastatic growth by androgen ablation[1]. Majority of patients eventually develop castration resistant prostate cancer (CRPC) which is typically androgen depletion resistant but androgen receptor (AR)-dependent[2]. In such cases, drugs that interfere with persistent intratumoral androgens provide an additional line of defense[3, 4]. The present study investigated differential expression of genes pertaining to the AR signaling pathway between BPH and prostate cancer patient samples, in anticipation that detection of specific genes and their associated components may provide the molecular cues underlying the mechanism of neoplastic development of the prostate gland and hold promises to eventually identify specific markers that demarcate disease states and progression
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