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Interaction of the Vitamin D Receptor with a Vitamin D Response Element in the Müllerian-Inhibiting Substance (MIS) Promoter: Regulation of MIS Expression by Calcitriol in Prostate Cancer Cells

Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

Address all correspondence and requests for reprints to: Peter J. Malloy, Ph.D., S025 Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5103. E-mail: malloy{at}cmgm.stanford.edu.

Calcitriol (1,25-dihydroxyvitamin D₃) inhibits the growth of a variety of cancer cells including human prostate cancer. Müllerian-inhibiting substance (MIS) also exhibits antiproliferative and proapoptotic actions on multiple cancer cells including human prostate cancer. In this study, we investigated whether calcitriol regulated MIS expression in prostate cancer, an action that might contribute to its antiproliferative activity. We identified a 15-bp sequence, GGGTGAgcaGGGACA, in the MIS promoter that was highly similar to direct repeat 3-type vitamin D response elements (VDREs). The human MIS promoter containing the putative VDRE was cloned into a luciferase reporter vector. In HeLa cells transfected with the vitamin D receptor (VDR), MIS promoter activity was stimulated by calcitriol. Coexpression of steroidogenic factor 1, a key regulator of MIS, increased basal MIS promoter activity that was further stimulated by calcitriol. Mutation or deletion of the VDRE reduced calcitriol-induced transactivation. In addition, the MIS VDRE conferred calcitriol responsiveness to a heterologous promoter. In gel shift assays, VDR and retinoid X receptor bound to the MIS VDRE and the binding was increased by calcitriol. Chromatin immunoprecipitation assays showed that VDR and retinoid X receptor were present on the MIS promoter in prostate cancer cells. In conclusion, we demonstrated that MIS is a target of calcitriol action. MIS is up-regulated by calcitriol via a functional VDRE that binds the VDR. Up-regulation of MIS by calcitriol may be an important component of the antiproliferative actions of calcitriol in some cancers.