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CRISPR-mediated reactivation of DKK3 expression attenuates TGF-β signaling in prostate cancer

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Kardooni, Hoda, Gonzalez-Gualda, Estela, Stylianakis, Emmanouil, Saffaran, Sina, Waxman, Jonathan and Kypta, Robert M. (2018) CRISPR-mediated reactivation of DKK3 expression attenuates TGF-β signaling in prostate cancer. Cancers, 10 (6). 165. doi:10.3390/cancers10060165

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Official URL: http://dx.doi.org/10.3390/cancers10060165

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Abstract

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 signalling.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science > Engineering
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Prostate -- Cancer -- Genetics, Tumors -- Growth -- Prevention, Homeostasis, Cancer cells -- Physiological aspects
Journal or Publication Title: Cancers
Publisher: MDPI
ISSN: 2072-6694
Official Date: 28 May 2018
Dates:
DateEvent
28 May 2018Published
24 May 2018Accepted
Volume: 10
Number: 6
Article Number: 165
DOI: 10.3390/cancers10060165
Status: Peer Reviewed
Publication Status: Published
Publisher Statement:
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDHarris Family Harvey Spack Memorial FundUNSPECIFIED
UNSPECIFIEDCancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIED[NIHR] National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
UNSPECIFIEDEkonomiaren Garapen eta Lehiakortasun Saila, Eusko Jaurlaritzahttp://dx.doi.org/10.13039/501100005004
UNSPECIFIEDDepartment of Innovation Technology of the Government of the Autonomous Community of the Basque CountryUNSPECIFIED
UNSPECIFIEDCentre of Excellence Severo Ochoa 2017-2021UNSPECIFIED
SAF2014-51966-R Ministerio de Ciencia e Innovaciónhttp://dx.doi.org/10.13039/501100004837
SAF2017-84092-RMinisterio de Ciencia e Innovaciónhttp://dx.doi.org/10.13039/501100004837

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