Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference
Melodie Grandin, Pauline Mathot, Guillaume Devailly, Yannick Bidet, Akram Ghantous, Clementine Fayrot, Benjamin Gibert, Nicolas Gadot, Isabelle Puisieux, Zdenko Herceg, Jean-Guy Delcros, Agnes Bernet, Patrick Mehlen, Robert Dante
EMBO MOLECULAR MEDICINE | WILEY-BLACKWELL | Published : 2016
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..View full abstract
We are grateful to Drs. A Puisieux and AP Morel for the HMLER cells and to Sandrine Viala for her nice and efficient work. We thank Dr B. Manship for editing of this manuscript and helpful discussions. This work was supported by institutional grants from the CNRS, the University of Lyon, the Centre Leon Berard, the Ligue Contre le Cancer, the INCA, the ANR, the ERC, the EC FP7 Hermione-2man and from the Fondation Bettencourt. MG was supported by a fellowship grant from the LabEx DEVweCAN.