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 language | English |
|---|---|
| Pages (from-to) | 2464-2477 |
| Number of pages | 14 |
| Journal | Oncogene |
| Volume | 33 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 2014 May 8 |
| Externally published | Yes |
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Keywords
- DKK1
- prostate cancer
- PTHrP
- skeletal metastasis
- Wnt/β-catenin signaling
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer. / Zhang, H.; Yu, C.; Dai, J.; Keller, J. M.; Hua, A.; Sottnik, J. L.; Shelley, G.; Hall, C. L.; Park, Serkin; Yao, Z.; Zhang, J.; McCauley, L. K.; Keller, E. T.
In: Oncogene, Vol. 33, No. 19, 08.05.2014, p. 2464-2477.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer
AU - Zhang, H.
AU - Yu, C.
AU - Dai, J.
AU - Keller, J. M.
AU - Hua, A.
AU - Sottnik, J. L.
AU - Shelley, G.
AU - Hall, C. L.
AU - Park, Serkin
AU - Yao, Z.
AU - Zhang, J.
AU - McCauley, L. K.
AU - Keller, E. T.
PY - 2014/5/8
Y1 - 2014/5/8
N2 - 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.
AB - 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.
KW - DKK1
KW - prostate cancer
KW - PTHrP
KW - skeletal metastasis
KW - Wnt/β-catenin signaling
UR - http://www.scopus.com/inward/record.url?scp=84900451130&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84900451130&partnerID=8YFLogxK
U2 - 10.1038/onc.2013.203
DO - 10.1038/onc.2013.203
M3 - Article
C2 - 23752183
AN - SCOPUS:84900451130
VL - 33
SP - 2464
EP - 2477
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 19
ER -