17β-Estradiol induces sulfotransferase 2A1 expression through estrogen receptor α.
Sulfotransferase (SULT) 2A1 catalyzes sulfonation of drugs and endogenous compounds and plays an important role in xenobiotic metabolism as well as in the maintenance of steroid and lipid homeostasis. A recent study showed that 17β-estradiol (E2) increases the mRNA levels of SULT2A1 in human hepatocytes. Here we report the underlying molecular mechanisms. E2 enhanced SULT2A1 expression in human hepatocytes and HepG2-ER cells (HepG2 stably expressing ERα). SULT2A1 induction by E2 was abrogated by antiestrogen ICI 182,780, indicating a key role of ERα in the induction. Results from deletion and mutation assays of SULT2A1 promoter revealed three cis-elements located within -257/+140 region of SULT2A1 that are potentially responsible for the induction. Chromatin immunoprecipitation assay verified the recruitment of ERα to the promoter region. Electrophoretic mobility shift assays revealed that AP-1 proteins bind to one of the cis-elements. Interestingly, SULT2A1 promoter assays using ERα mutants revealed that the DNA-binding domain of ERα is indispensable for SULT2A1 induction by E2, suggesting that direct ERα binding to the SULT2A1 promoter is also necessary for the induction. Taken together, our results indicate that E2 enhances SULT2A1 expression by both the classical and nonclassical mechanisms of ERα action.
Department of Pharmacy Practice (W.L., K.H.K., H.K., H.J.) and Department of Biopharmaceutical Sciences (M.N., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; and Medical College, Yangzhou University, Yangzhou, Jiangsu, China (W.L.).
Wei
W
Li
Miaoran
M
Ning
Kwi Hye
KH
Koh
Heesue
H
Kim
Hyunyoung
H
Jeong
D015153:Blotting, Western; D018929:Cell Culture Techniques; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004958:Estradiol; D015238:Sulfotransferases; C028152:alcohol sulfotransferase