Forkhead Box Protein A1 Regulates UDP-Glucuronosyltransferase 2B15 Gene Transcription in LNCaP Prostate Cancer Cells

Abstract

ABSTRACT:The UDP-glucuronosyltransferases (UGTs) 2B15 and 2B17 are the major UGTs involved in the inactivation and elimination of the active androgens, dihydrotestosterone and testosterone. Although regulation of these UGT genes by various endogenous and exogenous ligands, including steroid hormones and bile acids, is well documented, the mechanisms controlling their basal gene expression are poorly understood. We recently reported that Forkhead box protein A1 (FOXA1) regulates the basal expression of the UGT2B17 gene in prostate cancer cells. In this study, we show that FOXA1 also regulates basal expression of the UGT2B15 gene in the prostate cell line LNCaP (lymph node carcinoma of the prostate). FOXA1 binds to a site ؊208 to ؊217 base pairs relative to the UGT2B15 translation start site, as shown by electromobility shift and chromatin immunoprecipitation assays. Mutation of this site prevents binding and substantially decreases basal UGT2B15 promoter activity. Silencing of FOXA1 expression by small interfering RNA significantly reduced UGT2B15 transcript levels, further confirming a crucial role of FOXA1 in controlling UGT2B15 gene expression. Because local inactivation of active androgens by UGT2B15 and UGT2B17 has been shown to be a major determinant of androgen response and signaling activity, regulation of the UGT2B15 and UGT2B17 genes by FOXA1 may have an important role in the maintenance of androgen homeostasis within prostate cancer cells.

Fork head transcription factor is required for ovarian mature in the brown planthopper, Nilaparvata lugens (Stål)

“…In H. armigera , FoxA regulates the expression of diapause hormone [23]. In mammals, FoxA genes play crucial roles in multiple stages of mammalian life, including early development, organogenesis and differentiation, metabolism and homeostasis [21,44,45]. Fat body is a major tissue for vitellogenin synthesis during vitellogenesis [46].…”

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

“…Three days later, cells were treated for 24 hours with treatments as indicated. RNA extraction, reverse transcription, and qRT-PCR were performed as previously reported (11,15,16). For tissue samples, replicate pieces representing one condition were snap frozen in one tube containing RNAlater (Qiagen) and RNA isolated using RNeasy Kits (Qiagen) according to the manufacturer's protocol.…”

“…Steroid-induced transactivation of the proximal promoters of UGT2B15 and UGT2B17 Highly conserved estrogen response units (ERU) reside in the proximal promoters of the UGT2B15 and UGT2B17 genes, comprised of three estrogen response element (ERE) half-sites and two AP-1-binding sites, all required for E2-mediated transcriptional regulation (11). A FOXA1-binding site has recently been identified in the region between two of the ERE half-sites (11,16), but its importance in breast cancer cells is unknown. The prototypical ERU, including the FOXA1-binding UGT2B15 UGT2B17 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10…”

Gene Expression of Androgen Metabolising Enzymes in Benign and Malignant Prostatic Tissues

“…Intraprostatic levels of DHT are regulated by reductive and oxidative HSDs. AKR1C2 eliminates DHT by reducing it to the inactive androgen 5α-androstane-3α,17βdiol (3α-androstanediol), which is then glucuronidated to form 3α-androstanediol glucuronide by the UDP glycosyltransferase enzymes UGT2B15 or UGT2B17 [ 13 ] . Diseases of the prostate, for example, BPH and CaP, are prevalent in the aging male population, and display androgen-dependence when circulating T from the gonads decreases.…”