Specific inhibition of one DNMT1-including complex influences tumor initiation and progression.

Mathilde Cheray 1, 2 Romain Pacaud 1, 2 Arulraj Nadaradjane 1, 2 François Vallette 1, 2, 3 Pierre-François Cartron 1, 2, 4, *
* Auteur correspondant
4 CRCNA / Equipe 9 - Apoptose et Progression tumorale
Institut de Recherche en Santé de l'Université de Nantes (IRSUN), INSERM - Institut National de la Santé et de la Recherche Médicale : U892
Abstract : BACKGROUND: Reactivation of silenced tumor suppressor genes by DNMT inhibitors has provided an alternative approach to cancer therapy. However, DNMT inhibitors have also been shown to induce or enhance tumorigenesis via DNA hypomethylation-induced oncogene activation and chromosomal instability. To develop more specific DNMT inhibitors for efficient cancer therapy, we compared the effects of peptides designed to specifically disrupt the interaction of DNMT1 with different proteins. FINDINGS: Our data indicated that the use of an unspecific DNMT inhibitor (5aza-2deoxycytidine), a DNMT1 inhibitor (procainamide) or peptides disrupting the DNMT1/PCNA, DNMT1/EZH2, DNMT1/HDAC1, DNMT1/DNMT3b and DNMT1/HP1 interactions promoted or enhanced in vivo tumorigenesis in a mouse glioma model. In contrast, a peptide disrupting the DNMT1/DMAP1 interaction, which per se did not affect tumor growth, sensitized cancer cells to chemotherapy/irradiation-induced cell death. Finally, our data indicated that the peptide disrupting the DNMT1/DMAP1 interaction increased the efficiency of temozolomide treatment. CONCLUSION: Our data suggest that the DNMT1/DMAP1 interaction could be an effective anti-cancer target and opens a new avenue for the development of new strategies to design DNMT inhibitors.
Type de document :
Article dans une revue
Clinical Epigenetics, BioMed Central, 2013, 5 (1), pp.9. 〈10.1186/1868-7083-5-9〉
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Soumis le : mardi 13 août 2013 - 06:08:15
Dernière modification le : jeudi 5 avril 2018 - 10:36:33
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Mathilde Cheray, Romain Pacaud, Arulraj Nadaradjane, François Vallette, Pierre-François Cartron. Specific inhibition of one DNMT1-including complex influences tumor initiation and progression.. Clinical Epigenetics, BioMed Central, 2013, 5 (1), pp.9. 〈10.1186/1868-7083-5-9〉. 〈inserm-00851207〉

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