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Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference


Grandin, M; Mathot, P; Devailly, G; Bidet, Y; Ghantous, A; Favrot, C; Gibert, B; Gadot, N; Puisieux, I; Herceg, Z; Delcros, J; Bernet, A; Mehlen, P; Dante, R (2016). Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference. EMBO Molecular Medicine, 8(8):863-877.

Abstract

In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so-called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro-apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation-dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin-1 dependence receptor pro-apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin-1-low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti-netrin-1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin-1 neutralizing agents may be a valuable strategy for combating cancer.

Abstract

In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so-called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the selective inhibition of this dependence receptor death pathway relies on the silencing of pro-apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation-dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin-1 dependence receptor pro-apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin-1-low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti-netrin-1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin-1 neutralizing agents may be a valuable strategy for combating cancer.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Veterinary Clinic > Department of Small Animals
Dewey Decimal Classification:570 Life sciences; biology
630 Agriculture
Language:English
Date:2016
Deposited On:13 Oct 2016 12:31
Last Modified:08 Dec 2017 20:32
Publisher:Wiley Open Access
ISSN:1757-4676
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/emmm.201505945
PubMed ID:27378792

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