title: Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer.
abstract: Prostate cancer (PCa)bone metastases are unique in that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by PCa cells and intermittent PTHrP exposure has bone anabolic effects, suggesting that PTHrP could contribute to the excess bone mineralization. Wnts are bone-productive factors produced by PCa cells, and the Wnt inhibitor Dickkopfs-1 (DKK1) has been shown to promote PCa progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as PCa progresses, led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in PCa cells and, hence, allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a transcription factor (TCF) response element site. Furthermore, chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that PTHrP mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of β-catenin, which binds the most proximal DKK1 promoter, the TCF response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of PCa.
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA [2] Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry, Tianjin Medical University, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Keller
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Hua
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Sottnik
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Shelley
authors.affiliation: Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Hall
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Park
authors.affiliation: Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry, Tianjin Medical University, Tianjin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Center for Translational Medical Research, Guangxi Medical University, Guangxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA [2] Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: McCauley
authors.affiliation: 1] Department of Urology, School of Medicine, University of Michigan, Ann Arbor, MI, USA [2] Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Keller
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000528:radiation effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D044162:Parathyroid Hormone-Related Protein; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D051176:beta Catenin