Dickkopf-3 function in the prostate

Romero, Diana; Kypta, Robert M.

doi:10.4161/bioa.25243

Cited by 12 publications

(6 citation statements)

References 43 publications

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“…Notably, Dkk-3 inhibits MMP expression and activity, and MMP inhibitors rescue the effects of DKK3 knockdown on prostate epithelial cell acinar morphogenesis [ 15 ]. Based on these studies, we have proposed that endogenous Dkk-3 plays a protective role in prostate cancer by limiting TGF-β/Smad/MMP signaling [ 16 ]. However, the loss of Dkk-3 is anticipated to have effects on the activity and/or expression of other proteins in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

et al. 2018

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Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cell-conditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

et al. 2018

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“…Of note, the Dickkopf-related protein 3 (DKK3) gene, also known as ‘reduced expression in immortalized cells’ (REIC), is remarkably silenced by promoter methylation in many types of cancer, including PCa [ 13 , 14 , 15 ], particularly in high Gleason grade tumors [ 16 ]. The DKK3 gene product, Dickkopf-3 (Dkk-3), plays a role in prostate gland architecture [ 17 ] and displays potent tumor suppressor activity [ 18 ]. Ectopic expression of DKK3 in PCa cells leads to apoptosis [ 13 , 19 ] and inhibits proliferation, migration [ 15 , 20 ], and metastasis [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Kardooni

González-Gualda

Stylianakis

et al. 2018

Cancers

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The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.

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“…DKK3 overexpression in transfected cells resulted in a decrease in β-catenin expression (49). Inactivation of the DKK3 gene is also common in prostate cancer, in which the level of the Dkk3 protein is inversely correlated with the Gleason degree, and the lowest level was noted in tumors that are probably metastatic (51,52).…”

Section: Discussionmentioning

confidence: 99%

Differential gene methylation patterns in cancerous and non‑cancerous cells

Kamińska¹,

Białkowska²,

Kowalewski

et al. 2019

Oncol Rep

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Large-scale projects, such as The Cancer Genome Atlas (TCGA), Human Epigenome Project (HEP) and Human Epigenome Atlas (HEA), provide an insight into DNA methylation and histone modification markers. Changes in the epigenome significantly contribute to the initiation and progression of cancer. The goal of the present study was to characterize the prostate cancer malignant transformation model using the CpG island methylation pattern. The Human Prostate Cancer EpiTect Methyl II Signature PCR Array was used to evaluate the methylation status of 22 genes in prostate cancer cell lines: PC3, PC3M, PC3MPro4 and PC3MLN4, each representing different metastatic potential in vivo . Subsequently, it was ascertained whether DNA methylation plays a role in the expression of these genes in prostate cancer cells. Hypermethylation of APC, DKK3, GPX3, GSTP1, MGMT, PTGS2, RASSF1, TIMP2 and TNFRSF10D resulted in downregulation of their expression in prostate cancer cell lines as compared to WT fibroblasts. Mining of the TCGA data deposited in the MetHC database found increases in the methylation status of these 9 genes in prostate cancer patients, further supporting the role of methylation in altering the expression of these genes in prostate cancer. Future studies are warranted to investigate the role of these proteins in prostate cancer development.

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Dickkopf-3 function in the prostate

Cited by 12 publications

References 43 publications

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Differential gene methylation patterns in cancerous and non‑cancerous cells

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