RT Journal Article
SR Electronic
T1 Regulation of Human UDP-Glucuronosyltransferase 2B15 and 2B17 by miR-376c in prostate cancer cell lines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.226118
DO 10.1124/jpet.115.226118
A1 Dhilushi D Wijayakumara
A1 Dong Gui Hu
A1 Robyn Meech
A1 Ross A. McKinnon
A1 Peter Ian Mackenzie
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/07/10/jpet.115.226118.abstract
AB Given the prime importance of UGT2B15 and UGT2B17 in inactivating testosterone and dihydrotestosterone, control of their expression and activity in the prostate is essential for androgen signalling homeostasis in that organ. Although several studies provide evidence of transcriptional control of UGT2B15 and UGT2B17 by various endogenous and exogenous compounds, potential post-transcriptional regulation of UGT2B15 and UGT2B17 by microRNAs in prostate cancer cells has not been examined. The present study identified a putative miR-376c target site in the 3'-untranslated regions (UTR) of both UGT2B15 and UGT2B17 mRNAs. In accord with the possibility that this miRNA negatively regulates UGT2B15 and UGT2B17 expression, there is an inverse correlation in the levels of miR-376c and UGT2B15/UGT2B17 mRNAs in prostate cancer cell lines versus normal prostate tissue. In LNCaP cells, transfection of miR-376c mimics inhibited the glucuronidations of testosterone, 4-methylumbelliferone (a substrate of UGT2B15) and androsterone (a substrate of UGT2B17). MiR-376c reduced both UGT2B15 and UGT2B17 mRNA and protein levels, and the activity of luciferase reporters containing UGT2B15 or UGT2B17 3'-UTRs. This microRNA-mediated repression was significantly abrogated by mutating the miR-376c binding site in the 3’-UTRs of both UGTs. Collectively, these data indicate that the expression of UGT2B15 and UGT2B17 is negatively regulated by the binding of miR-376c to the 3'-UTRs of UGT2B15 and UGT2B17 in prostate cancer cells. This represents the first evidence for post-transcriptional regulation of UGT2B15 and UGT2B17 by miRNAs in prostate cancer cells and may have importance in regulating androgen receptor signalling.