Abstract 361: Calcitriol-dependent induction of the human sulfotransferase SULT2B1 in the prostate: Implication in the growth inhibition of prostate cancer
Authors: Song Chung Seog , Seo Young-Kyo , Echchgadda Ibtissam , Chatterjee Bandana 
Published: June 2012

Abstract
Background: The sulfotransferase (SULT) family of cytosolic enzymes catalyzes the sulfate conjugation of structurally diverse hormones, neurotransmitters, drugs and xenobiotic chemicals. Individual SULT members differ in tissue distributions and substrate specificity. SULT2B1 is a SULT2 subfamily hydroxysteroid sulfotransferase expressed as -a and -b isoforms, which are splice variants of a single gene, albeit with distinct substrate specificities and tissue distributions. The CNS-expressed -a isoform sulfonates pregnenolone and it is devoid of cholesterol sulfonation activity. The second isoform (SULT2B1b) is most abundant in the skin, prostate and placenta, and has specificity for both cholesterol and the pro-androgen DHEA (dehydroepiandrosterone). SULT2B1b expression is high in the normal prostate, BPH prostate, in prostate tumors and in prostate cancer cell lines. The cholesterol- and DHEA-specific activity of the prostate-expressed SULT2B1, and the inability of the sulfated androgen to bind the androgen receptor suggest that SULT2B1 activity can potentially regulate prostate cell growth by limiting the availability of active androgens. Results: We show that the gene encoding SULT2B1 is induced by calcitriol (1,25-dihydroxy vitamin D3) in prostate cancer cell lines and in the mouse prostate. This induction involves engagement of the agonist-bound vitamin D receptor (VDR) at a calcitriol-induced region in the SULT2B1 promoter, revealed from chromatin immunoprecipitation (ChIP) assay using calcitriol-treated prostate cancer cells and prostate tissues from calcitriol- or EB1089- (a VDR agonist) injected mice. The human SULT2B1 gene promoter, introduced in mice through the tail vein, was induced in the prostate and skin of calcitriol-injected mice. The promoter was not induced in the liver. The VDR responsive element (VDRE) in the SULT2B1 promoter is configured as a direct repeat of the consensus half site AGGTCA. This VDRE resides within the first 250 bases of the upstream promoter of the human SULT2B1. Binding of VDR to this element was confirmed by gel mobility shift and DNase1 footprinting assay using nuclear extracts from the human and mouse prostate. Binding sites for additional factors are juxtaposed to the VDRE. Point mutations within VDRE abrogated binding of the VDR/RXR-α heterodimer and prevented induction of the SULT2B1 promoter by the ligand-activated VDR. Conclusion: The calcitriol-mediated inhibition of the androgen-induced growth of prostate cancer cells is thought to involve multiple mechanisms, including induction of the CDK2 inhibitor p21 and the nucleus to cytoplasm mislocaliztion of CDK2. Our results described here suggest that induction of SULT2B1 is an additional mechanism by which calcitriol interferes with the androgen/androgen receptor pathway in the prostate.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 361. doi:10.1158/1538-7445.AM2011-361