Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer

H. Zhang, C. Yu, J. Dai, J. M. Keller, A. Hua, J. L. Sottnik, G. Shelley, C. L. Hall, S. I. Park, Z. Yao, J. Zhang, L. K. McCauley, E. T. Keller

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2464-2477
Number of pages14
JournalOncogene
Volume33
Issue number19
DOIs
Publication statusPublished - 2014 May 8

Keywords

  • DKK1
  • PTHrP
  • Wnt/β-catenin signaling
  • prostate cancer
  • skeletal metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Zhang, H., Yu, C., Dai, J., Keller, J. M., Hua, A., Sottnik, J. L., Shelley, G., Hall, C. L., Park, S. I., Yao, Z., Zhang, J., McCauley, L. K., & Keller, E. T. (2014). Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer. Oncogene, 33(19), 2464-2477. https://doi.org/10.1038/onc.2013.203