Perspective on the regulatory role of UGT2B28 as a conjugating enzyme in the progression of prostate cancer

Abstract

: The maintenance of steroid homeostasis in the prostate is critical, with perturbation of steroidogenesis contributing to the modulation of active ligands in the androgen pool. In this scenario, enzymes catalysing the biosynthesis, inactivation and conjugation of steroids are the key players, regulating active ligand levels and in so doing, the activation of the androgen receptor (AR). The glucuronidation of potent ligands renders them unable to bind the AR, allowing the secretion of conjugated steroids. Uridine diphosphate glucuronosyltransferase 2B type 28 (UGT2B28), one of the UGT enzymes catalyzing the glucuronidation of androgens, has recently been given a prominent role in the regulation of prostate steroidogenesis—one which stands in contrast to the accepted dogma that lower androgen levels resulting from increased conjugation are associated with decreased prostate cancer (PCa) risk and disease progression. Increased DHT and its precursors, T and androstenediol, were reported to be associated with increased UGT2B28 tumor expression levels, linked to lower PSA levels but higher Gleason scores and increased PCa risk. In addition, the complete deletion of UGT2B28, was associated with decreased T, DHT and glucuronide derivatives when compared to patients carrying both alleles. UGT2B28 is encoded by a single gene giving rise to UGT2B28 type I which catalyses androgen glucuronidation and, due to alternative splicing, also produces two distinct transcripts, UGT2B28 type II and III. Type II with its premature stop codon, is devoid of the cofactor binding domain while type III is devoid of the substrate binding domain, both catalytically inactive, truncated proteins. Increased UGT2B28 mRNA expression was reported in primary tumours, and while variable nuclear and strong cytoplasmic staining were distinctive of tumour cells, the expression levels and compartmentalization of the specific protein isoforms remain unknown. While increased expression of type I would contribute towards lowering androgen levels, increased expression of types II and III would not. The abundance of type III transcripts in multiple tissues may provide insight into a regulatory role with truncated isoforms possibly affecting androgen levels by regulating substrate and/or co-factor availability, dimerization or the formation of protein complexes with other UGTs, while protein-protein interaction may also impact cascade signaling pathways in PCa development and disease progression.