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Article Dans Une Revue EMBO Molecular Medicine Année : 2016

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

Résumé

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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Dates et versions

hal-01792610 , version 1 (05-09-2018)

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Paternité - Pas d'utilisation commerciale

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M. Grandin, P. Mathot, Guillaume Devailly, Y. Bidet, Akram Ghantous, et al.. Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference. EMBO Molecular Medicine, 2016, 8 (8), pp.863-877. ⟨10.15252/emmm.201505945⟩. ⟨hal-01792610⟩
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