Abstract
BackgroundPerturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution.MethodsWe conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data.ResultsUGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa.ConclusionsThe androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.
Highlights
Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression
UGT2B17 subcellular localisation is altered in PCa compared with normal peritumoural glands We initially investigated the expression and cellular distribution of UGT2B17 in benign prostatic tissue and in prostate tumours using the monoclonal anti-UGT2B17 antibody (EL-2B17mAb), for which the specificity was recently reported.[24]
UGT2B17 expression in relation to androgen receptor (AR) expression and the functional variation in the proximal promoter FOXA1-binding site Based on previous findings of UGT2B17 regulation involving the AR in the PCa cell line LNCaP,[37,38] we examined the potential correlation between AR and UGT2B17 expression in clinical samples
Summary
Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. Uridine diphospho-glucuronosyltransferase enzymes (UGTs) are responsible for the inactivation of various endogenous signalling molecules, including androgens and oestrogens.[10] UGT enzymes are located in the membranes of the endoplasmic reticulum and glycosylate their steroid substrates with glucuronic acid,[11] an enzymatic reaction referred to as glucuronidation This results in glucuronide (–G) derivatives that are more hydrophilic than the parent molecules, and can be more excreted into bile or urine.[10] Glucuronidation is an essential pathway for steroid inactivation and elimination in cancer cells, and is very active in the prostate.[12] the UGT pathway participates in the regulation of the local exposure of prostate cells to steroid hormones, and this pathway has been shown to influence the risk[13,14] and progression of PCa.[15,16,17]
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