Epigenetic regulation of UDP-Glucuronosyltransferases

Several lines of recent evidence suggest that the steroidogenic enzymes responsible for the catabolism of intraprostatic testosterone metabolites are important to biochemical recurrence and progression to castration-resistant prostate cancer (CRPC) (Santer et al., 2015; Mitra and Goodman, 2015; Mitsiades, 2013; Levesque et al., 2013; Crawford, 2009; Titus et al., 2014;, Taplin et al., 2008).  UGT2B7, UGT2B15, and UGT2B17 enzymes exhibit substrate specificity for the glucuronidation of intraprostatic testosterone and testosterone metabolites dihydrotestosterone (DHT), androsterone and 5?-androstane-3?,17?-diol (Turgeon et al., 2001). Thus, the regulation of the expression of UGT2B enzymes is critical for the normal hormonal microenvironment in prostate and other tissues.  Recent evidence suggests that UGT2B7 enzymes form homodimers that are capable of catalyzing glucuronidation (Lewis et al., 2011).  The dimerization occurs via an eighteen amino acid domain that is present in all known UGT2B enzymes.  We hypothesize that the UGT2B15 enzymes forms multiple enzyme complexes that bind to chromatin as part of epigenetic regulation of gene expression. Previous studies have shown that UGT2B15 is negatively regulate in prostate cancer metastases and CRPC tumors suggesting that loss of expression may be important for prostate tumor progression (Gauthier-Landry et al., 2015). Important for this proposed study is that preliminary evidence shows that UGT2B15 is expressed in nuclear and chromatin protein fractions of the LNCaP prostate cancer cell line. Further, immunoprecipitation of nuclear extracts from those cells using UGT2B15 antibodies produces a protein complex of higher molecular weight than the native UGT2B15 protein.  We will use the UGT2B15 as a model to determine for the first time if drug detoxifying enzymes are involved in cis- or trans-gene regulation.  The results from this study will help elucidate the mechanism by which hormone perturbations occur that lead to prostate cancer progression in CRPC.