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

被引:25
作者
Grandin, Melodie [1 ]
Mathot, Pauline [1 ]
Devailly, Guillaume [1 ]
Bidet, Yannick [2 ]
Ghantous, Akram [3 ]
Fayrot, Clementine [1 ]
Gibert, Benjamin [1 ]
Gadot, Nicolas [4 ]
Puisieux, Isabelle [5 ]
Herceg, Zdenko [3 ]
Delcros, Jean-Guy [1 ]
Bernet, Agnes [1 ]
Mehlen, Patrick [1 ]
Dante, Robert [1 ]
机构
[1] Uriversite Lyon, Ctr Leon Berard, Canc & Dev Lab,CRCL,INSERM U1052,CNRS UMR5286, Dependence Receptors,Equipe Labellisee La Ligue,L, Lyon, France
[2] Ctr Jean Perrin, Lab Oncol Mol, Clermont Ferrand, France
[3] IARC, Epigenet Grp, Lyon, France
[4] Univ Lyor, Hop Edouard Herriot, Hosp Civils Lyon, Endocrine Differentiat Lab,CRCL,Anat Pathol, Lyon, France
[5] UCBL, CLB, Targeting Tumor & Its Immure Environm Lab CRCL, INSERM U1052,CNRS UMR5286, Lyon, France
关键词
apoptosis; breast cancer; decitabine; dependence receptor; DNA methylation; CELL LUNG-CANCER; MAMMARY EPITHELIAL-CELLS; DCC GENE-PRODUCT; EPIGENETIC THERAPY; INDUCED APOPTOSIS; SURVIVAL FACTOR; DAP-KINASE; RECEPTOR; DEATH; TRANSFORMATION;
D O I
10.15252/emmm.201505945
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:863 / 877
页数:15
相关论文
共 45 条
  • [1] Specific binding of the methyl binding domain protein 2 at the BRCA1-NBR2 locus
    Auriol, E
    Billard, LM
    Magdinier, F
    Dante, R
    [J]. NUCLEIC ACIDS RESEARCH, 2005, 33 (13) : 4243 - 4254
  • [2] The future of epigenetic therapy in solid tumours-lessons from the past
    Azad, Nilofer
    Zahnow, Cynthia A.
    Rudin, Charles M.
    Baylin, Stephen B.
    [J]. NATURE REVIEWS CLINICAL ONCOLOGY, 2013, 10 (05) : 256 - 266
  • [3] Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?
    Baylin, SB
    Ohm, JE
    [J]. NATURE REVIEWS CANCER, 2006, 6 (02) : 107 - 116
  • [4] Inactivation of the UNC5C netrin-1 receptor is associated with tumor progression in colorectal malignancies
    Bernet, Agnes
    Mazelin, Laetitia
    Coissieux, Marie-May
    Gadot, Nicolas
    Ackerman, Susan L.
    Scoazec, Jean-Yves
    Mehlen, Patrick
    [J]. GASTROENTEROLOGY, 2007, 133 (06) : 1840 - 1848
  • [5] The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites
    Beygo, Jasmin
    Citro, Valentina
    Sparago, Angela
    De Crescenzo, Agostina
    Cerrato, Flavia
    Heitmann, Melanie
    Rademacher, Katrin
    Guala, Andrea
    Enklaar, Thorsten
    Anichini, Cecilia
    Silengo, Margherita Cirillo
    Graf, Notker
    Prawitt, Dirk
    Cubellis, Maria Vittoria
    Horsthemke, Bernhard
    Buiting, Karin
    Riccio, Andrea
    [J]. HUMAN MOLECULAR GENETICS, 2013, 22 (03) : 544 - 557
  • [6] The neuroimmune guidance cue netrin-1: A new therapeutic target in cardiovascular disease
    Bongo, Joseph Bertrand
    Peng, Dao Quan
    [J]. JOURNAL OF CARDIOLOGY, 2014, 63 (1-2) : 95 - 98
  • [7] Netrins: beyond the brain
    Cirulli, Vincenzo
    Yebra, Mayra
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (04) : 296 - 306
  • [8] Cancer Epigenetics: From Mechanism to Therapy
    Dawson, Mark A.
    Kouzarides, Tony
    [J]. CELL, 2012, 150 (01) : 12 - 27
  • [9] Netrin-1 acts as a survival factor for aggressive neuroblastoma
    Delloye-Bourgeois, Celine
    Fitamant, Julien
    Paradisi, Andrea
    Cappellen, David
    Douc-Rasy, Setha
    Raquin, Marie-Anne
    Stupack, Dwayne
    Nakagawara, Akira
    Rousseau, Raphael
    Combaret, Valerie
    Puisieux, Alain
    Valteau-Couanet, Dominique
    Benard, Jean
    Bernet, Agnes
    Mehlen, Patrick
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (04) : 833 - 847
  • [10] Interference With Netrin-1 and Tumor Cell Death in Non-Small Cell Lung Cancer
    Delloye-Bourgeois, Celine
    Brambilla, Elisabeth
    Coissieux, Marie-May
    Guenebeaud, Celine
    Pedeux, Remy
    Firlej, Virginie
    Cabon, Florence
    Brambilla, Christian
    Mehlen, Patrick
    Bernet, Agnes
    [J]. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2009, 101 (04): : 237 - 247