Specific inhibition of one DNMT1-including complex influences tumor initiationand progression

Clinical Epigenetics

Pierre-François Cartron³  François M Vallette¹  Arulraj Nadaradjane²  Romain Pacaud²  Mathilde Cheray² 

[1] LaBCT, Institut de Cancérologie de l'Ouest, Boulevard J Monod, Nantes,Saint Herblain Cedex, 44805, France;Département de Recherche en Cancérologie, Université deNantes, Faculté de Médecine, IFR26, Nantes, F-4400, France;Institut de Recherche Thérapeutique INSERM U892 – CRCNA, Equipe 9–Apoptose et Progression tumorale, 8 Quai Moncousu, BP 70721, Nantes,Cedex 1, 44007, France

关键词: Cell death;    GBM;    Glioma;    DNA methylation;    Epigenetic;    DNMT1;   

Others  :  790980
DOI  :  10.1186/1868-7083-5-9

 received in 2013-03-19, accepted in 2013-06-03,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Cheray et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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